Pharmaceutical compositions of nilotinib

ABSTRACT

Amorphous solid dispersions of nilotinib fumarate or nilotinib tartrate are provided, as well as pharmaceutical compositions thereof, wherein the compositions exhibit enhanced bioavailability in the fasted state. Preferably, the compositions may be orally administered to a patient in either the fed or fasted state, with a decrease or elimination of the food effect. Preferably, following oral administration of the pharmaceutical compositions, there is no substantial difference in the pharmacokinetic parameters (e.g., Cmax, AUC0-t and/or AUC0-infinity) of nilotinib, regardless of whether the pharmaceutical compositions are administered to a subject in the fed or fasted state.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a Continuation of copending application Ser. No.16/953,728 filed on Nov. 20, 2020, which is a Continuation ofapplication Ser. No. 16/793,833 filed on Feb. 18, 2020, now U.S. Pat.No. 10,874,671 issued on Dec. 29, 2020, which claims foreign priority toIndian Application No. IN 201941006393, filed on Feb. 18, 2019, which isincorporated by reference in its entirety.

FIELD OF THE INVENTION

Amorphous solid dispersions of nilotinib fumarate or nilotinib tartrateare provided, as well as pharmaceutical compositions thereof, whereinthe inventive compositions exhibit enhanced bioavailability in thefasted state compared to a reference formulation. Preferably, thepharmaceutical compositions eliminate or reduce the food effect, suchthat they may be administered without regard to food. The compositionmay preferably comprise a granulate material that can be filled into acapsule or compressed into a tablet.

The present application also provides methods for treating proliferationdisorders in a human subject, such as chronic myeloid leukemia andgastrointestinal stromal tumours, by administering a pharmaceuticallyeffective amount of the pharmaceutical composition.

BACKGROUND OF THE INVENTION

Nilotinib is chemically described as4-methyl-N-[3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl] amino]-benzamide and is aninhibitor of protein tyrosine kinase (TK), and in particular, it is aselective inhibitor of Bcr-Abl tyrosine kinase. Examples of conditionsthat may be treated by nilotinib include, but are not limited to,chronic myeloid leukemia and gastrointestinal stromal tumours.

Nilotinib is characterized as a Biopharmaceutical Classification System(BCS) class IV compound, which means that it has low/moderate aqueoussolubility and low permeability. The solubility of nilotinib at 25° C.in aqueous solutions decreases strongly with increasing pH and it ispractically insoluble at pH 4.5 and higher. This decrease in thesolubility of nilotinib in environments with a pH of more than 1.0 leadsto a decrease in the absorption of nilotinib. Nilotinib hydrochloride ispoorly water soluble and hence, it would be difficult to formulate anddeliver oral dosage forms which exhibit good bioavailability.

Nilotinib is currently marketed under the brand name TASIGNA®. TASIGNA®is available in the form of hard gelatin capsules containing nilotinibhydrochloride monohydrate equivalent to 50 mg, 150 mg and 200 mg ofnilotinib. The package insert of TASIGNA® reveals that the patients areinstructed to take the capsules twice daily at approximately 12-hourintervals. TASIGNA® is prescribed as 300 mg twice daily (600 mg totaldaily dose) for treatment of newly diagnosed philadelphia chromosomepositive chronic myeloid leukemia and 400 mg twice daily (800 mg totaldaily dose) for treatment resistant or intolerant philadelphiachromosome positive chronic myelogenous leukemia.

The bioavailability of TASIGNA® is increased when given with a meal.Compared to the fasted state, the systemic exposure (AUC) is reported toincrease by 82% when the dose is given 30 minutes after a high fat meal.In order to minimize the food effect, the label indicates that it isnecessary to administer the capsules on an empty stomach. Therefore, nofood should be consumed for at least 2 hours before the dose is takenand for at least 1 hour after the dose is taken.

Commercially available preparations of nilotinib pose risk of adverseeffects, particularly if the patient ingests the tablets of nilotinibwith or after meals, particularly high fat meals, because the rate andextent of absorption (area under the plasma profile curve and theC_(max)) are increased by 82% and 112%, respectively. (Castagnetti etal; Hematology Meeting Reports, 2008; 2 (5); 22-26).

It is desirable to have a composition for oral administration whichprovides nilotinib to a patient population with lower variability inbioavailability, thus providing consistent PK parameters (e.g., anarrower observed range for C_(max) and AUC values) across patientpopulation to whom the formulation is administered.

Moreover, it is also desirable to have a composition for oraladministration which provides enhanced nilotinib bioavailabilitycompared to commercially available formulation, i.e., TASIGNA®, thusyielding higher plasma levels in fasted state.

In addition, it is also desirable to have a composition for oraladministration which provides an acceptable plasma level of nilotinibwhen administered to a patient in fed state.

Thus, what is needed is a nilotinib composition that is suitable fororal administration to patients, and which provides uniform plasmalevel(s) and sufficient nilotinib exposure (AUC) in fasted and fedstates. What is also needed is a nilotinib oral composition whichexhibit less variability in pharmacokinetic parameters (e.g., C_(max),AUC_(0-t) and AUC_(0-infinity)) than commercially available nilotinibformulation (TASIGNA®).

There exists a need for nilotinib oral compositions which exhibitimproved bioavailability in fasting state and also exhibit lessvariability in pharmacokinetic parameters (e.g., C_(max), AUC_(0-t) andAUC_(0-infinity)) in fasted and fed states, than a reference product,i.e. commercially available nilotinib formulation (TASIGNA®). There alsoexists a need for administering reduced daily doses of nilotinib,wherein the compositions exhibit enhanced bioavailability in fastedstate and can be administered without regard to food.

Furthermore, solid dispersions of poorly soluble drugs in polymers aregenerally unstable over time. Amorphous solid dispersions especiallytend to convert to crystalline forms over time, which can lead toimproper dosing due to differences of the bioavailability and solubilityof crystalline drug material compared to amorphous drug material. Oneskilled in the art cannot predict which carriers, if any, would beuseful for preparing stable amorphous dispersions for a particular drugproduct.

Hence, there exists a need to provide compositions suitable for oraladministration comprising stable amorphous solid dispersions ofnilotinib or its pharmaceutically acceptable salts, wherein thecompositions exhibit enhanced bioavailability in the fasted state, andwhich can be administered without regard to food.

SUMMARY OF THE INVENTION

The present invention relates to pharmaceutical compositions comprisingamorphous solid dispersion of nilotinib or pharmaceutically acceptablesalts thereof (e.g., nilotinib fumarate or nilotinib tartrate) for oraladministration, wherein the composition exhibits enhancedbioavailability in the fasted state and may be administered withoutregard to food.

The present application provides pharmaceutical compositions ofnilotinib or its pharmaceutically acceptable salts thereof (e.g.,nilotinib fumarate or nilotinib tartrate), of reduced strength/dose ascompared to the dose of reference formulation, wherein the compositioneliminates or reduces the food effect.

In an embodiment, the dose of nilotinib administered to a human subjectis reduced by at least 10% in comparison to a reference formulationwhich is current marketed formulation of nilotinib (i.e., TASIGNA®). Inyet another embodiment, the dose of nilotinib administered to a humansubject is reduced by at least 50% in comparison to a referenceformulation which is current marketed formulation of nilotinib (i.e.,TASIGNA®).

The present application further provides pharmaceutical compositions ofnilotinib exhibiting a mean C_(max) and AUC under fasting conditionwhich is at least about 2 to 2.5 times higher than the mean C_(max) andAUC of TASIGNA® under fasting condition.

The present application further provides pharmaceutical compositions ofnilotinib fumarate or nilotinib tartrate having enhanced bioavailabilityin comparison to the current marketed formulation of nilotinib (i.e.,TASIGNA®) in fasted state and still be bioequivalent to TASIGNA® underfed and fasting conditions.

Solid dispersions, methods of making solid dispersions, methods ofmaking pharmaceutical compositions, and methods of treatment using thepharmaceutical compositions described are also provided.

The present application provides amorphous solid dispersions comprisingnilotinib fumarate or nilotinib tartrate. Pharmaceutical compositionsare also provided, which comprise an effective amount of amorphous soliddispersion of nilotinib fumarate or nilotinib tartrate, wherein thesolid dispersion comprises a pharmaceutically acceptable carrier andoptionally at least one organic acid, and wherein the pharmaceuticalcomposition provides enhanced bioavailability when compared to areference formulation in fasted state.

The pharmaceutical compositions preferably comprise an effective amountof amorphous solid dispersion of nilotinib fumarate or nilotinibtartrate, wherein the solid dispersion further comprises apharmaceutically acceptable carrier and optionally at least one organicacid, and wherein at least one pharmacokinetic parameter of nilotinib ina human subject subsequent to administration in the fasted state is fromabout 80% to about 125% of that pharmacokinetic parameter of nilotinibin a human subject subsequent to administration in the fed state,wherein at least one pharmacokinetic parameter is selected fromAUC_(0-infinity), C_(max), AUC_(0-t), or combinations thereof.

Each of embodiments described in this application may further have oneor more of the following additional elements in any combination:

Element 1: the amorphous solid dispersions may further comprise apharmaceutically acceptable carrier, and optionally, at least oneorganic acid.

Element 2: the amorphous solid dispersions may be prepared by hot-meltextrusion, spray-drying or co-precipitation.

Element 3: the amorphous solid dispersions may have a weight ratio ofthe nilotinib fumarate or the nilotinib tartrate, respectively, to thepharmaceutically acceptable carrier from about 1:1 to about 1:6,preferably from about 1:3 to about 1:4.

Element 4: the amorphous solid dispersions may comprise, consistessentially of or consist of a pharmaceutically acceptable carrierselected from the group consisting of hydroxypropyl methyl celluloseacetate succinate (HPMC-AS), polyvinyl pyrrolidine and vinyl acetate(PVPNA) copolymer, hydroxypropyl methylcellulose phthalate (HPMCP),hydroxypropyl methylcellulose (HPMC), polyethylene glycol (PEG),hydroxypropyl cellulose (HPC), carboxymethyl cellulose (CMC), polyvinylpyrrolidine (PVP), and mixtures thereof.

Element 5: the amorphous solid dispersions may optionally contain anorganic acid, and the organic acid may be selected from the groupconsisting of acetic acid, propionic acid, octanoic acid, decanoic acid,dodecanoic acid, glycolic acid, lactic acid, fumaric acid, succinicacid, adipic acid, pimelic acid, malic acid, tartaric acid, citric acid,glutamic acid, aspartic acid, maleic acid, benzoic acid, salicylic acid,phthalic acid, phenylacetic acid, cinnamic acid, ascorbic acid, andmixtures thereof.

Element 6: the amorphous solid dispersions may have nilotinib fumarateor the nilotinib tartrate present in a weight ratio relative to theorganic acid of about 1:0.5 to about 1:5, preferably present in a ratioof about 1:2, more preferably present in a ratio of about 1:1.

Element 7: the amorphous solid dispersions may further comprise one ormore pharmaceutically acceptable excipients selected from the groupconsisting of diluents, binders, disintegrants, lubricants, glidants,surfactants, solubilizers, plasticizers, stabilizing agents,antioxidants and combinations thereof.

Element 8: the pharmaceutical compositions may comprise from about 25 mgto about 200 mg of nilotinib fumarate or nilotinib tartrate.

Element 9: the pharmaceutical compositions may preferably be in the formof a tablet, a capsule, a caplet, beads, granules or oral suspension.

Element 10: the pharmaceutical compositions may further comprise one ormore pharmaceutically acceptable excipients selected from the groupconsisting of diluents, binders, disintegrants, lubricants, glidants,surfactants, plasticizers, solubilizers, stabilizing agents,antioxidants and combinations thereof.

Element 11: the pharmaceutical compositions may preferably be obtainedby direct compression, wet granulation or dry granulation.

Element 12: the pharmaceutical compositions may preferably be in theform of a tablet comprising: (a) an amorphous solid dispersion ofnilotinib fumarate or nilotinib tartrate, for example, in the form ofgranules, (b) at least one intra-granular excipient, (c) at least oneextra-granular excipient, and (d) optionally, a coating.

Element 13: the solid dispersions or pharmaceutical compositions maypreferably remain stable under accelerated conditions, e.g., thecompositions remain stable for at least 6 months at 40° C./75% RH(“relative humidity”) or 25° C./60% RH (“relative humidity”).

Element 14: the solid dispersions or pharmaceutical compositionspreferably have a level of any unknown impurity that is less than about0.2% (w/w), preferably less than about 0.15% (w/w), and more preferablyless than about 0.1% (w/w) as measured by HPLC.

Element 15: the solid dispersions and pharmaceutical compositions maypreferably be made by (a) dry-blending nilotinib fumarate or nilotinibtartrate and at least one pharmaceutically acceptable carrier selectedfrom the group consisting of hydroxypropyl methyl cellulose acetatesuccinate (HPMC-AS), polyvinyl pyrrolidine and vinyl acetate (PVP/VA)copolymer, hydroxypropyl methylcellulose phthalate (HPMCP),hydroxypropyl methylcellulose(HPMC), polyethylene glycol(PEG),hydroxypropyl cellulose(HPC), carboxymethyl cellulose(CMC), polyvinylpyrrolidine (PVP), and combinations thereof, to form a mixture; (b)heating the mixture to a temperature sufficient to form a moltendispersion, wherein the melting is carried out under a temperature from80° C. to 200° C. and a screw speed from 30 to 1000 rpm; and (c)extruding the molten dispersion to provide a composition comprising asolid dispersion of nilotinib in at least one pharmaceuticallyacceptable carrier. The process may further comprise the steps of: (d)milling the composition from (c) to provide granules comprisingnilotinib fumarate or nilotinib tartrate; (e) mixing the granules from(d) with an extra-granular mixture comprising one or more excipientsselected from the group consisting of crospovidone, colloidal silica,magnesium stearate, and mixtures thereof, to provide a blend; (f)compressing the blend into tablets or filling the blend into a capsuleshell; and (g) optionally, coating the tablets or capsule shell.

Element 16: the solid dispersions and pharmaceutical compositions maypreferably be included in a kit comprising: (a) a pharmaceuticalcomposition according to the invention; and (b) instructions for oraladministration of the composition, wherein the instructions indicatethat the composition can be administered to a human subject withoutregard to food.

Element 17: the solid dispersions and pharmaceutical compositions maypreferably be used in a method for treating a proliferative disorder ina human subject, which method comprises: (a) providing a pharmaceuticalcomposition; and (b) providing instructions for oral administration ofthe composition indicating that the composition can be administered to ahuman subject without regard to food.

By way of non-limiting example, exemplary combinations applicable to theembodiments described in this application may include any combinationwith one or more of the elements described above.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates powder X-ray diffraction patterns of composition 2and 5 from Example 1.

FIG. 2 illustrates the powder X-ray diffraction pattern of the amorphoussolid dispersion of nilotinib fumarate according to Composition 13 fromExample 3.

FIG. 3 illustrates powder X-ray diffraction pattern of Composition 16from Example 4.

FIG. 4 illustrates comparative dissolution profiles of TASIGNA® 50 mgcapsule and Composition 34 and 35 in 0.01 M HCl acid media followed byFeSSIF media of pH 5.0±0.05.

FIG. 5 illustrates comparative dissolution profiles of TASIGNA® 50 mgcapsule and Composition 36 in 0.01 M HCl acid media followed by buffermedia of FeSSIF or FaSSIF.

FIG. 6 illustrates comparative dissolution profiles of TASIGNA® 50 mgcapsule and Composition 50 and 51 in 0.01 M HCl acid media followed byFeSSIF media of pH 5.0±0.05.

FIG. 7 illustrates comparative dissolution profile of TASIGNA® 50 mgcapsule and Composition 52 in 0.01 M HCl acid media and followed bydouble strength FaSSIF media.

FIG. 8 illustrates comparative dissolution profiles of TASIGNA® 50 mgcapsule and Composition 53 in 0.01 M HCl acid media and followed byFaSSIF buffer media of pH 6.5±0.05 or followed by FeSSIF buffer media ofpH 5.0±0.05.

FIG. 9 illustrates comparative dissolution profiles of TASIGNA® 50 mgcapsule, Composition 54 and 55 in 0.01 N HCl acid media and followed byFaSSIF buffer media of pH 6.5±0.05.

DETAILED DESCRIPTION OF THE INVENTION

Unless defined otherwise, all the technical and scientific terms usedherein have the same meanings as commonly known by a person skilled inthe art. In case of conflict, the definitions provided herein willprevail. Unless specified otherwise, all the percentages, portions andratios in the present invention are on weight basis.

The terms “about” and “approximate,” when used along with a numericalvariable, generally means the value of the variable and all the valuesof the variable within a measurement or an experimental error (e.g., 95%confidence interval for the mean) or within a specified value (e.g.,±10%) within a broader range.

As used herein the term “nilotinib” refers to nilotinib free base or itspharmaceutically acceptable salts, solvates or hydrates thereof. Inprinciple, any crystalline form of nilotinib or amorphous form ofnilotinib may be used for manufacturing the pharmaceutical compositionof the present invention.

The term “pharmaceutically acceptable” substances means those, which,according to a common medical judgment, are suitable to be in contactwith a tissue of a patient without any inappropriate toxicity,irritation, allergic response, etc., have a reasonable balance betweenadvantages and disadvantages, and can be applied to its target useeffectively.

The term “pharmaceutically acceptable salt” refers to nilotinib saltswhich are formed with inorganic acids or organic acids. Suitable saltsinclude salts formed with organic acids such as citric acid, tartaricacid, or fumaric acid.

The terms “pharmaceutical composition,” “pharmaceutical product,”“pharmaceutical dosage form,” “dosage form,” “pharmaceuticalformulation,” etc., refer to a pharmaceutical composition administeredto a patient in need of treatment, which is typically in the form ofpowder, granules, pill, beads, capsule, caplet, tablet, oral suspensionetc.

The terms “carrier” and “pharmaceutically acceptable carrier” areinterchangeable. The carrier is able to form a matrix embedding(surrounding) the active ingredient. The matrix may comprise one carrieror a mixture of two or more carriers. The carrier used in the soliddispersion of the present invention may be an enteric polymer ornon-enteric polymer.

According to the embodiments of the invention, the pharmaceuticallyacceptable carrier is selected from one or more of hydroxypropyl methylcellulose acetate succinate (HPMC-AS), polyvinyl pyrrolidine and vinylacetate (PVPNA) copolymer, hydroxypropyl methylcellulose phthalate(HPMCP), hydroxypropyl methylcellulose (HPMC), polyethylene glycol(PEG), hydroxypropyl cellulose (HPC), carboxymethyl cellulose (CMC), andpolyvinyl pyrrolidine (PVP).

According to the embodiments of the invention, the hydroxypropylmethylcellulose acetate succinate (HPMC-AS) comprises various types,such as LF, LG, MF, MG, HF and HG, etc., the first letters L, M and H ofthe type's names mean the pH level at the beginning of dissolution ofHPMC-AS. For example, L refers to low level (e.g., HPMC-AS begins to bedissolved when the pH value is more than 5.5), M refers to middle level(e.g., HPMC-AS begins to be dissolved when the pH value is more than6.0), H refers to high level (e.g., HPMC-AS begins to be dissolved whenthe pH value is more than 6.5). The second letters F and G refer to theparticle size of HPMC-AS, where F refers to fine powder, and G refers togranular. In some embodiments, the type of HPMC-AS is LF; in someembodiments, the type of HPMC-AS is MF; in some embodiments, the type ofHPMC-AS is HG.

By “solid dispersion” is meant a molecular dispersion of a compound,particularly a drug substance within a carrier. The term soliddispersion in general means a system in solid state comprising at leasttwo components, wherein one component is dispersed substantially evenlythroughout the other component(s). For example, solid dispersions may bethe dispersion of one or more active ingredients in an inert carrier ormatrix at solid state, prepared by the melting, solvent, ormelting-solvent methods. While not wishing to be bound by theory, in asolid dispersion, the drug may be present in a molecular state,colloidal state, metastable state, or an amorphous state. Formation of amolecular dispersion may provide a means of reducing the particle sizeto nearly molecular levels (i.e., there are no particles).

The term “solubility” means solubility of nilotinib or itspharmaceutically acceptable salts in aqueous media such as water,buffer, gastrointestinal simulated fluid, gastrointestinal fluid and thelike.

The term “in vivo” in general means in the living body of a plant oranimal, whereas the term “in vitro” generally means outside the body andin an artificial environment.

As used herein, the term “reference formulation” is a formulation thatis used for comparison. Preferably, the reference formulation may referto an oral dosage form containing 50 mg, 150 mg or 200 mg of nilotinibhydrochloride. Preferably, the reference formulation corresponds to anoral dosage form of nilotinib, which is currently marketed under thebrand name TASIGNA®.

The term “subject” refers to an animal, including a human or non-human(e.g., beagle dogs). The terms patient and subject may be usedinterchangeably herein.

Enhanced Bioavailability and Reduced/Eliminated Food Effect

The term “bioavailability” indicates the extent to which a drug oranother substance is utilized by a target tissue after administration.For example, “bioavailability” may refer to the fraction of drugabsorbed following administration to a subject or patient underfed orfasted state. In certain aspects, under fasted state, thebioavailability of nilotinib when formulated as described herein is atleast about 15%, but may be greater than 20%, 25%, 30%, 35%, 40%, 45%,or 50% of the dose administered.

The term “peak time of plasma drug concentration (T_(max))” means thetime when peak plasma drug concentration (C_(max)) is attained afterdrug administration.

The term “peak plasma drug concentration (C_(max))” means the maximumplasma drug concentration attained after drug administration.

The term “AUC_(0-infinity)” means the area under a plasma drugconcentration-time curve from time point of 0 to infinity after drugadministration, and the term “AUC_(0-t)” means the area under a plasmadrug concentration-time curve from time point of 0 to t after drugadministration.

As used herein, the term “enhanced bioavailability” refers to increasein concentration of the active ingredient in the body fluid provided bythe compositions of the present invention when compared to concentrationof the active ingredient in the body fluid obtained from a referenceformulation under identical conditions. In certain aspects, under fastedstate, the bioavailability of nilotinib when formulated as describedherein is enhanced at least about 15%, but may be greater than 20%, 25%,30%, 35%, 40%, 45%, or 50% of the dose administered when compared to areference formulation under identical conditions.

Reference throughout this specification will be made to theadministration of a pharmaceutical composition underfed conditions orfasted conditions. It is well understood in the art that thepharmacokinetic performance of some compositions is affected by thepresence or absence of food in the gastro-intestinal system. Thesereferences thus relate to the normally accepted administrationcircumstances that are referred to in the art as “fed” or “fasted.”

As used herein, the term “fasted state” means that the human or othermammal has not ingested 500 calories or more than 500 calories for atleast two hours before taking nilotinib solid oral dosage form and forat least two hours after taking nilotinib solid oral dosage form.

As used herein, the term “fed state” refers to a human who has eaten aUnited States Food and Drug Administration (FDA) standard high fatbreakfast (or other meal containing a comparable quantity of fat andcalories) within said time period. The meal is high in both fat(approximately 50% of total calorie content of the meal) and calories(approximately 800-1000 calories).

The term “food effect” as used herein means food-drug interactions whicheither decrease or increase the extent of drug absorption. In otherwords the bioavailability for a drug is altered when administered underfasted state, in comparison to the drug when administered in the fedstate. It may refer to a relative difference in one or more of AUC_(∞),AUC_(0-t) and/or C_(max) of a drug, when said drug or a formulationthereof is administered orally to a human, concomitantly with food or ina fed state as compared to the same values when the same formulation isadministered in a fasted state or without food.

In certain aspects, the food effect may be defined as the ratio of theC_(max) and/or AUC values of the tested drug in fed versus fastedstates. Measuring the C_(max) and/or AUC values of the tested drug infed and in fasted states is standard practice in the art. Reduction offood effect can be determined by comparing the value of the ratio fromthe composition or pharmaceutical composition of the invention and thevalue of a composition without the solubilized form disclosed in thepresent invention.

In certain aspects, the pharmaceutical compositions described hereinreduce or eliminate the food effect. As used herein, “reducing the foodeffect” refers to narrowing the difference in bioavailability, e.g.,AUC_(∞), AUC_(0-t) and/or C_(max) for a drug administered under fastedstates in comparison to the drug administered under fed states. Incertain aspects, the food effect is eliminated. Thus, upon oraladministration of a pharmaceutical composition as described herein, to amammal in need thereof, there is not a significant food effect. In otherwords, the difference between a pharmacokinetic parameter measured afteroral administration to a mammal with and without food, respectively, isless than 40%, e.g., less than 35%, less than 30%, less than 25%, lessthan 20%, less than 15%, less than 10 or less than 5%. Preferably thecomposition or the pharmaceutical composition of the invention has atleast 15% reduced food effect, preferably 20%, preferably 25%,preferably 30%, preferably 40%, reduced food effect.

Pharmacokinetic parameters for the compositions can be measured in asingle or multiple dose study using a replicate or a non-replicatedesign. For example, the pharmacokinetic parameters can be measured in asingle dose pharmacokinetic study using a two-period, two-sequencecrossover design. Alternately, a four-period, replicate design crossoverstudy may also be used. Pharmacokinetic parameters characterizing rateand extent of nilotinib absorption are evaluated statistically. The areaunder the plasma concentration-time curve from time zero to the time ofmeasurement of the last quantifiable concentration (AUC_(0-t)) and toinfinity (AUC_(0-infinity)), C_(max), and T_(max) can be determinedaccording to standard techniques. Statistical analysis ofpharmacokinetic data is performed on logarithmic transformed data (e.g.,AUC_(0-t), AUC_(0-infinity), or C_(max) data) using analysis of variance(ANOVA).

The difference in AUC of the compositions of the present invention, whenadministered in the fed versus the fasted state, preferably is less thanabout 100%, less than about 90%, less than about 80%, less than about70%, less than about 65%, less than about 60%, less than about 55%, lessthan about 50%, less than about 45%, less than about 40%, less thanabout 35%, less than about 30%, less than about 25%, less than about20%, less than about 15%, less than about 10%, less than about 5%, orless than about 3%.

The difference in C_(max) of the compositions of the present invention,when administered in fed versus the fasted state, preferably is lessthan about 100%, less than about 90%, less than about 80%, less thanabout 70%, less than about 65%, less than about 60%, less than about55%, less than about 50%, less than about 45%, less than about 40%, lessthan about 35%, less than about 30%, less than about 25%, less thanabout 20%, less than about 15%, less than about 10%, less than about 5%,or less than about 3%.

In some aspects, following administration of the pharmaceuticalcomposition to subjects (e.g., fed subjects or fasted subjects), themean bioavailability is greater than about 20% (e.g., greater than 25%,30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, oreven 99%) or between about 20% to about 90% (e.g., from 20% to 30%, from20% to 40%, from 20% to 50%, from 20% to 60%, from 20% to 70%, from 20%to 80%, from 20% to 90%, from 30% to 40%, from 30% to 50%, from 30% to60%, from 30% to 70%, from 30% to 80%, from 30% to 90%, from 40% to 50%,from 40% to 60%, from 40% to 70%, from 40% to 80%, from 40% to 90%, from50% to 60%, from 50% to 70%, from 50% to 80%, from 50% to 90%, from 60%to 70%, from 60% to 80%, from 60% to 90%, from 70% to 80%, from 70% to90%, and from 80% to 90%).

In some aspects, the ratio of the mean bioavailability for fed subjectsto the mean bioavailability for fasted subjects is from about 1.0 toabout 2.0 (e.g., from 1.0 to 1.1, from 1.0 to 1.2, from 1.0 to 1.3, from1.0 to 1.4, from 1.0 to 1.5, from 1.0 to 1.6, from 1.0 to 1.7, from 1.0to 1.8, from 1.0 to 1.9, from 1.3 to 1.4, from 1.3 to 1.5, from 1.3 to1.6, from 1.3 to 1.7, from 1.3 to 1.8, from 1.3 to 1.9, from 1.3 to 2.0,from 1.5 to 1.6, from 1.5 to 1.7, from 1.5 to 1.8, from 1.5 to 1.9, from1.5 to 2.0, from 1.7 to 1.8, from 1.7 to 1.9, from 1.7 to 2.0, from 1.8to 1.9, and from 1.8 to 2.0).

In some aspects, administration of the pharmaceutical composition to fedand fasted subjects produces a coefficient of variation in AUC_(0-t),T_(max), C_(max) and/or AUC_(∞) of less than about 60% (e.g., less than55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, and 15%). In particularembodiments, the coefficient of variation in C_(max) and/or AUC_(∞) isof from about 20% to about 60% (e.g., from 20% to 30%, from 20% to 35%,from 20% to 40%, from 20% to 45%, from 20% to 50%, from 20% to 55%, from30% to 35%, from 30% to 40%, from 30% to 45%, from 30% to 50%, from 30%to 55%, from 30% to 60%, from 35% to 40%, from 35% to 45%, from 35% to50%, from 35% to 55%, from 35% to 60%, from 40% to 45%, from 40% to 50%,from 40% to 55%, from 40% to 60%, from 45% to 50%, from 45% to 55%, from45% to 60%, from 50% to 55%, from 50% to 60%, and from 55% to 60%).

In some aspects, administration of the pharmaceutical composition to afasted subject produces mean C_(max) that is greater than about 100ng/mL (e.g., greater than about 150 ng/mL, 200 ng/mL, 250 ng/mL, 300ng/mL, 350 ng/mL, 400 ng/mL, 450 ng/mL, 500 ng/mL, 550 ng/mL, 600 ng/mL,650 ng/mL, 700 ng/mL, 750 ng/mL, 800 ng/mL, 850 ng/mL, 900 ng/mL, 950ng/mL, and/or up to about 1000 ng/mL) for a 50 mg equivalent dose ofnilotinib.

In some aspects, administration of the pharmaceutical composition to afasted subject produces mean AUC_(0-∞) that is greater than about 1500hr*ng/mL (e.g., greater than 1500 hr*ng/mL, 1600 hr*ng/mL, 1700hr*ng/mL, 1800 hr*ng/mL, 1900 hr*ng/mL, 2000 hr*ng/mL, 2100 hr*ng/mL,2200 hr*ng/mL, 2300 hr*ng/mL, 2400 hr*ng/mL, 2500 hr*ng/mL, 2600hr*ng/mL, 2700 hr*ng/mL, 2800 hr*ng/mL, 2900 hr*ng/mL and/or greaterthan about 3000 hr*ng/mL) for a 50 mg equivalent dose of nilotinib.

Pharmaceutically Acceptable Salts of Nilotinib

Pharmaceutically acceptable salts of nilotinib may be formed as acidaddition salts, for example with organic or inorganic acids.

Suitable inorganic acids include, but are not limited to, halogen acids,such as hydrochloric acid, sulfuric acid, or phosphoric acid.

Suitable organic acids are, for example, carboxylic, phosphonic,sulfonic or sulfamic acids, for example acetic acid, propionic acid,octanoic acid, decanoic acid, dodecanoic acid, glycolic acid, lacticacid, fumaric acid, succinic acid, adipic acid, pimelic acid, malicacid, tartaric acid, citric acid, amino acids, such as glutamic acid oraspartic acid, maleic acid, benzoic acid, salicylic acid, cinnamic acid,or other organic protonic acids, such as ascorbic acid. Useful salts ofnilotinib for preparing inventive compositions herein are nilotinibtartrate and nilotinib fumarate.

Solid Dispersions of Nilotinib

The term “solid dispersion” refers to a system in a solid-statecomprising at least two components, wherein one component is dispersedthroughout the other component or components.

The solid dispersions of nilotinib may be formed by any conventionaltechnique, e.g., spray drying, co-grinding, hot melt extrusion, freezedrying, rotary evaporation, solvent evaporation, co-precipitation,lyophilization, or any suitable solvent removal process. In anembodiment, solid dispersions of nilotinib of the present applicationcomprises crystalline and/or amorphous forms of nilotinib free base or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.

The nilotinib starting material used in the process for preparation ofthe solid dispersion may be crystalline or amorphous form.Alternatively, it may be obtained in situ from a previous processingstep.

The nilotinib in the solid dispersion obtained may be present in eithercrystalline or amorphous form.

A solid that is in the “amorphous” solid state form means that it is ina non-crystalline state. Amorphous solids generally possess crystal-likeshort-range molecular arrangement, but no long-range order of molecularpacking as are found in crystalline solids. The solid-state form of asolid, such as the drug substance in the amorphous dispersion, may bedetermined by Polarized Light Microscopy, X-Ray Powder Diffraction(XPRD), Differential Scanning Calorimetry (DSC), or other standardtechniques known to those of skill in the art. Preferably, the amorphoussolid contains drug substance in a substantially amorphous solid-stateform, e.g., at least about 80% of the drug substance in the dispersionis in an amorphous form, more preferably at least about 90% of the drugsubstance in the dispersion is in an amorphous form, and most preferablyat least about 95% of the drug substance in the dispersion is inamorphous form.

In some embodiments, at least about 90% (e.g., at least 95%, 96%, 97%,98%, 99%, 99.5%, or even 99.9%, such as from 90% to 99.9%, from 90% to99.5%, from 90% to 99%, from 90% to 98%, from 90% to 97%, from 90% to96%, from 90% to 95%, from 95% to 99.9%, from 95% to 99.5%, from 95% to99%, from 95% to 98%, from 95% to 97%, and from 95% to 96%) of thenilotinib is in amorphous form.

The solid dispersion can be in a single phase such as substitutional orinterstitial crystalline solutions or amorphous solutions; or it can bea two-phase system such as eutectics, crystalline drug and amorphouscarrier or amorphous drug and amorphous carrier dispersions. Solidsolutions are a resultant single phase upon dispersion of two compoundsin each other, at their molecular level.

The inventors of the present application have found that a compositioncomprising amorphous solid dispersion of nilotinib or itspharmaceutically acceptable salts comprising at least onepharmaceutically acceptable carrier and at least one organic acid at acertain ratio, can increase the solubility of nilotinib ingastrointestinal tract, and can ameliorate the problem of precipitationor crystallization, thereby increasing the absorption of nilotinib invivo and bioavailability thereof.

In another aspect, the composition can alter the absorption behavior ofnilotinib in vivo, increasing C_(max) and AUC without prolonging T_(max)in fasted state.

In certain aspects, a pharmaceutically acceptable carrier used in thesolid dispersion may be an enteric or a non-enteric polymer.

The enteric polymers are selected from the group consisting of celluloseacetate phthalate, cellulose acetate trimellitate, cellulose acetatesuccinate, methyl cellulose phthalate, ethylhydroxymethylcellulosephthalate, hydroxypropylmethylcellulose phthalate (HPMCP),hydroxypropylmethyl cellulose acetate succinate (HPMC-AS),hydroxypropylmethyl cellulose acetate maleate,hydroxypropylmethylcellulose trimellitate, carboxymethylethyl cellulose,polyvinyl butyrate phthalate, polyvinyl acetate phthalate, a methacrylicacid/ethyl acrylate copolymer and a methacrylic acid/methyl methacrylatecopolymer, preferably selected from the group consisting of HPMCP,HPMC-AS, hydroxypropylmethyl cellulose acetate maleate andhydroxypropylmethylcellulose trimellitate, and more preferably isHPMC-AS.

The non-enteric polymers are selected from the group consisting ofhydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethylcellulose, polyvinylpyrrolidone (povidone),poly(vinylpyrrolidone/vinylacetate) (copovidone),polyvinylcaprolactam/polyvinylacetate/polyethylene glycol graftcopolymer, polyethylene glycol/polyvinyl alcohol graft copolymer,polyethylene oxide, polypropylene oxide, copolymers of ethylene oxideand propylene oxide, polyvinyl alcohol, partially saponifiedpolyvinylalcohol, macrogolglycerol hydroxystearate, polyethylene glycol,and maltodextrins.

In some aspects, the pharmaceutical composition includes amorphous soliddispersion of the nilotinib or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable carrier, where the weightratio of the nilotinib or a pharmaceutically acceptable salt thereof, tothe pharmaceutically acceptable carrier is from about 1:6 to about 1:1(e.g., from 1:6 to 1:2, from 1:6 to 1:2.5, from 1:6 to 1:3, from 1:6 to1:3.5, from 1:6 to 1:4, from 1:6 to 1:4.5, from 1:6 to 1:5, from 1:5 to1:2, from 1:5 to 1:2.5, from 1:5 to 1:3, from 1:5 to 1:3.5, from 1:5 to1:4, from 1:5 to 1:4.5, from 1:5 to 1:1.5, from 1:4 to 1:1.5, from 1:4to 1:2, from 1:4 to 1:2.5, from 1:4 to 1:3, from 1:4 to 1:3.5, from 1:3to 1:1.5, from 1:3 to 1:2, from 1:3 to 1:2.5, and from 1:2 to 1:1.5).

In certain embodiments, nilotinib or its pharmaceutically acceptablesalt and pharmaceutically acceptable carrier are present in a ratio ofabout 1:1 to about 1:6 (w/w), about 1:1 to about 1:4 (w/w), preferablyin the ratio of about 1:3 (w/w).

Solid dispersions of the present invention optionally may include one ormore organic acids. The organic acid may be selected from acetic acid,propionic acid, octanoic acid, decanoic acid, dodecanoic acid, glycolicacid, lactic acid, fumaric acid, succinic acid, adipic acid, pimelicacid, malic acid, tartaric acid, citric acid, glutamic acid, asparticacid, maleic acid, benzoic acid, salicylic acid, phthalic acid,phenylacetic acid, cinnamic acid and ascorbic acid. The concentration oforganic acid in the inventive compositions may range from about 10 mg toabout 300 mg.

In embodiments, nilotinib or its pharmaceutically acceptable salt andorganic acid are present in a ratio of 1:0.5 to 1:5, preferably presentin a ratio of 1:2, more preferably present in a ratio of 1:1.

Solid dispersions of the present invention optionally may include one ormore solubilizers, i.e., additives which increase solubility of thepharmaceutical active ingredient in the solid dispersion or additiveswhich act as pore-forming agents in the solid dispersion. Suitablesolubilizers for use in compositions of the present invention includemannitol, transcutol, polyvinylalcohol, hydroxypropyl methylcellulose,hydroxypropyl cellulose, polyvinylpyrrolidone, glycofurol andtranscutol. The concentration of solubilizer ranges from about 1% toabout 30% w/w of carrier concentration.

The amorphous solid dispersions of the present invention optionally mayinclude one or more surfactants. Surfactants are compounds which arecapable of improving the wetting of the drug and/or enhancing thedissolution. The surfactants can be selected from hydrophilicsurfactants or lipophilic surfactants or mixtures thereof. Thesurfactants can be anionic, nonionic, cationic, and zwitterionicsurfactants. Surfactants according to the present invention include, butnot limited to, polyoxyethylene alkylaryl ethers such as polyoxyethylenelauryl ether, polyoxyethylene cetyl ether, polyoxyethylene stearylether; polyethylene glycol fatty acid esters such as PEG monolaurate,PEG dilaurate, PEG distearate, PEG dioleate; polyoxyethylene sorbitanfatty acid ester such as polysorbate 40, polysorbate 60, polysorbate 80;sorbitan fatty acid mono esters such as sorbitan monolaurate, sorbitanmonooleate, sorbitan sesquioleate, sorbitan trioleate, sodium laurylsulfate, sodium dioctyl sulfosuccinate (DOSS), lecithin, stearylicalcohol, cetostearylic alcohol, cholesterol, polyoxyethylene ricin oil,polyoxyethylene fatty acid glycerides, cremophor RH 40, and the like orcombinations thereof. The concentration of surfactant ranges from about1% to about 10% w/w of carrier concentration.

In some aspects herein, the percentage loading of nilotinib fumarate ornilotinib tartrate in solid dispersion is from about 1% to about 90%(w/w) (e.g., from 1% to 19%, from 10% to 19%, from 10% to 20%, from 10%to 30%, from 10% to 40%, from 10% to 50%, from 10% to 60%, from 10% to70%, from 10% to 80%, from 10% to 90%, from 20% to 30%, from 20% to 40%,from 20% to 50%, from 20% to 60%, from 20% to 70%, from 20% to 80%, from20% to 90%, from 21% to 30%, from 21% to 34%, from 21% to 40%, from 21%to 50%, from 21% to 60%, from 21% to 70%, from 21% to 80%, from 21% to90%, from 30% to 40%, from 30% to 50%, from 30% to 60%, from 30% to 70%,from 30% to 80%, from 30% to 90%, from 36% to 40%, from 36% to 49%, from36% to 60%, from 36% to 70%, from 36% to 80%, from 36% to 90%, from 40%to 50%, from 40% to 60%, from 40% to 70%, from 40% to 80%, from 40% to90%, from 50% to 60%, from 50% to 70%, from 50% to 80%, from 50% to 90%,51% to 60%, from 51% to 70%, from 51% to 80%, from 51% to 90%, from 60%to 70%, from 60% to 80%, from 60% to 90%, from 70% to 80%, and from 70%to 90%). In some preferred embodiments, the percentage loading ofnilotinib fumarate or nilotinib tartrate is from about 10% to about 60%(w/w) (e.g., from 10% to 20%, from 10% to 30%, from 10% to 40%, from 10%to 50%, from 10% to 60%, from 20% to 30%, from 20% to 40%, from 20% to50%, from 20% to 60%, from 30% to 40%, from 30% to 50%, from 30% to 60%,from 40% to 50%, and from 40% to 60%).

Solid dispersions of the present application are obtained by one or moreof methods selected from spray-drying, solvent evaporation,co-precipitation, hot melt extrusion, co-grinding and lyophilization.The solid dispersions obtained by the present application may be presenteither in crystalline form or in amorphous form.

In an embodiment, amorphous solid dispersions of nilotinib or itspharmaceutically acceptable salts are obtained by hot melt extrusion.The term hot-melt extrusion or hot-melt extruded is used herein todescribe a process whereby a composition is heated and/or compressed toa molten (or softened) state and subsequently forced through an orificein a die where the extruded product is formed into its final shape inwhich it solidifies upon cooling. The blend is conveyed through one ormore heating zones typically by a screw mechanism. The screw or screwsare rotated by a variable speed motor inside a cylindrical barrel whereonly a small gap exists between the outside diameter of the screw andthe inside diameter of the barrel. In this conformation, high shear iscreated at the barrel wall and between the screw fights by which thevarious components of the powder blend are well mixed and disaggregated.The die can be a dual manifold, multi-manifold or feed-block style die.

The hot-melt extrusion used for the preparation of the pharmaceuticalcomposition of the present invention has to be conducted at temperaturesbelow 200° C. Preferably, the hot-melt extrusion is conducted at atemperature of 30-170° C., more preferred at a temperature of 120-160°C. The hot-melt extrusion has to be carried out at a temperature thatallows the dissolution of the nilotinib or its pharmaceuticallyacceptable salts used as staring material within the mixture of entericpolymer and optionally at least one organic acid.

In an embodiment, amorphous solid dispersions of nilotinib or itspharmaceutically acceptable salts are obtained by spray drying process.Spray dried dispersions are obtained by dissolving drug and the carrierin an organic solvent and then spray-drying the solution. Theformulation and process conditions are chosen so that the solventquickly evaporates from the droplets, allowing insufficient time forphase separation or crystallization.

In an embodiment, nilotinib or its pharmaceutically acceptable salt, atleast one enteric polymer and optionally at least one organic acid aremixed with one or more of organic solvents. Suitable solvents for mixingare selected from methanol, ethanol, isopropanol (IPA), ethyl acetate,dichloromethane (DCM), ethylene chloride, chloroform, acetonitrile,acetone and mixtures thereof.

In an embodiment, spray dried amorphous solid dispersions of nilotinibor its pharmaceutically acceptable salts are obtained by a processcomprising; mixing nilotinib or its pharmaceutically acceptable salt, atleast one enteric polymer and optionally at least one organic acid in amixture of DCM and methanol (1:1) and spray drying the solution usingspray drier. In another embodiment, spray dried amorphous soliddispersions of nilotinib are obtained by a process comprising; mixingnilotinib or its pharmaceutically acceptable salt, at least one entericpolymer and optionally at least one organic acid in methanol and spraydrying the solution using spray drier. The spray drying equipment,solvent quantities and process conditions are selected by one skilled inthe art based on requirements.

The resultant amorphous solid dispersions of nilotinib fumarate ornilotinib tartrate can be blended with one or more excipients, asdescribed herein, and then granulated and/or compacted to produce afinal blend for encapsulating or tableting. In particular embodiments,the amorphous solid dispersion of nilotinib may be combined with one ormore excipient(s) may be included to form granules, e.g., such as abinding agent, a filler, a disintegrating agent, a wetting agent, aglidant, and a lubricant.

Pharmaceutical Compositions Comprising Solid Dispersions of Nilotinib

The solid dispersion may be used for filling any one of the unit dosageforms described herein (e.g., a capsule) or for tableting. The soliddispersion can optionally be further processed before filling ortableting. Exemplary further processing includes spheronizing,pelletizing, milling, injection molding, sieving, and/or calendering thesolid dispersion.

Amorphous solid dispersions of nilotinib or its pharmaceuticallyacceptable salts of the present application can be optionally subjectedto a particle size reduction procedure before or after the completion ofdrying of the product to produce desired particle sizes anddistributions. Milling or micronization can be performed to achieve thedesired particle sizes or distributions. Equipment that may be used forparticle size reduction include, without limitation thereto, ball mills,roller mills, hammer mills, and jet mills.

In another general aspect, there is provided solid dispersion ofnilotinib comprising amorphous form of nilotinib having particle sizedistributions wherein D90 is less than about 500 microns or less thanabout 200 microns or less than about 100 microns or less than about 50microns or less than about 40 microns or less than about 30 microns orless than about 20 microns or less than about 10 microns or any othersuitable particle sizes.

The amorphous solid dispersion of nilotinib fumarate or nilotinibtartrate may be combined with pharmaceutically acceptable excipients tomake other pharmaceutical compositions, or a finished dosage form. Theone or more additional pharmaceutically acceptable excipients areselected from diluents, binders, disintegrants, lubricants, glidants,surfactants, solubilizers, stabilizing agents, antioxidants, colors,flavors, preservatives, and combinations thereof.

In an embodiment, pharmaceutical compositions comprising amorphous soliddispersion of nilotinib fumarate or nilotinib tartrate andpharmaceutically acceptable excipients are prepared by using, but notlimited, to wet granulation, dry granulation, and direct compression.

In an embodiment, pharmaceutical compositions comprising amorphous soliddispersion of nilotinib or pharmaceutically acceptable salts thereof andpharmaceutically acceptable excipients are prepared by using directcompression, which process comprises mixing amorphous solid dispersionof nilotinib and pharmaceutically acceptable excipients, the resultantmixture is either compressed to tablet or filled in hard gelatincapsules.

In an embodiment, pharmaceutical compositions comprising amorphous soliddispersion of nilotinib fumarate or nilotinib tartrate andpharmaceutically acceptable excipients are prepared by using drygranulation, wherein dry granulation is carried out by either directcompaction or roller compaction or both.

In an embodiment, pharmaceutical compositions comprising amorphous soliddispersion of nilotinib fumarate or nilotinib tartrate andpharmaceutically acceptable excipients are prepared by using directcompaction dry granulation, which process comprises compressing mixtureof amorphous solid dispersion of nilotinib fumarate or nilotinibtartrate and intragranular material into slug, compressed slugs aremilled and passed through mess screen manually or automatically whichresults in granules. The resulting granules were mixed withextra-granular material. This final mixture is either compressed totablet or filled in hard gelatin capsules.

In an embodiment, pharmaceutical compositions comprising amorphous soliddispersion of nilotinib fumarate or nilotinib tartrate andpharmaceutically acceptable excipients are prepared by using rollercompaction dry granulation, which process comprises passing a mixture ofamorphous solid dispersion of nilotinib fumarate or nilotinib tartrateand intragranular material between two high-pressure rollers to formconsolidated and densified material, the resultant densified material isthen reduced to a uniform granule size by milling, which were then mixedwith extra-granular material. This final mixture is either compressed totablet or filled in hard gelatin capsules.

In an embodiment, pharmaceutical compositions comprising amorphous soliddispersion of nilotinib fumarate or nilotinib tartrate andpharmaceutically acceptable excipients are prepared by wet granulation,which process comprises: (a) mixing amorphous solid dispersion ofnilotinib fumarate or nilotinib tartrate and pharmaceutically acceptableexcipients (b) adding sufficient solvent, wherein the solvent isselected form water, isopropanol, ethanol, to the mixture obtained fromstep (a) under shear to generate granules; (c) milling or grinding thegranules followed by sieving of said granules; optionally mixing withother excipients. This final mixture is either compressed to tablet orfilled in hard gelatin capsules.

The invention also relates to compositions comprising amorphous soliddispersion of nilotinib fumarate or nilotinib tartrate for oraladministration, which solid dispersion further comprises at least onepharmaceutically acceptable carrier and optionally at least one organicacid, which composition comprises (a) an immediate-release portion and(b) a modified-release portion, wherein the organic acid may be presenteither in immediate-release or modified-release portion or may bepresent in both the portions.

As used herein the term “immediate-release” refers to the rapid releaseof the majority of the therapeutic compound. Particularly usefulconditions for immediate-release are release of at least or equal toabout 80% of the therapeutic compound within thirty minutes after oralingestion. The particular immediate-release conditions for a specifictherapeutic compound will be recognized or known by one of ordinaryskill in the art.

As used herein the term “modified-release” refers to slower release ofthe majority of the therapeutic compound as compared to immediaterelease dosage forms. The particular modified-release conditions for aspecific therapeutic compound will be recognized or known by one ofordinary skill in the art.

The compositions are manufactured by processes such as directcompression, wet granulation or dry granulation. The pharmaceuticalcompositions are in the form of oral dosage forms, preferably solid oraldosage forms, including capsules, tablets and multi-particulates.

Physically, the combination of active ingredient and vehicle may eitherform a solid dispersion, i.e., the active ingredient is dispersed in thevehicle in particulate form, or may form a solid solution, i.e., theactive ingredient is dissolved in the vehicle at a molecular level. Theactive ingredient and the vehicle may also form a solid dispersionhaving therein a part of the active ingredient dissolved at a molecularlevel. The physical state of the dispersion and/or solution may bedetermined by using various techniques such as Hot Stage Microscopy(HSM), Differential Scanning Calorimetry (DSC), Scanning ElectronMicroscopy (SEM) optionally in combination with Energy Dispersive X-ray(EDX), and X-ray powder diffraction.

In an embodiment, inventive amorphous solid dispersions of nilotinibtartrate of the present application comprise nilotinib tartrate, atleast one enteric polymer and at least one organic acid, wherein theenteric polymer is HPMC-AS and the organic acid is tartaric acid.Specifically, nilotinib tartrate and HPMC-AS are present in a ratio of1:3 (w/w), nilotinib tartrate and tartaric acid are present in a ratioof 1:1 (w/w).

In an embodiment, inventive amorphous solid dispersions of nilotinibfumarate of the present application comprise nilotinib fumarate, atleast one enteric polymer and at least one organic acid, wherein theenteric polymer is HPMC-AS and the organic acid is fumaric acid.Specifically, nilotinib fumarate and HPMC-AS are present in a ratio of1:3 (w/w), nilotinib fumarate and fumaric acid are present in a ratio of1:1 (w/w).

An embodiment relates to pharmaceutical compositions comprisingamorphous solid dispersions of nilotinib fumarate or nilotinib tartratefor oral administration, wherein at least 30% of nilotinib fumarate ornilotinib tartrate is released within 60 minutes as determined by USPdissolution apparatus II (paddle) at 75 rotations per minute (rpm) in500 mL of 0.01 M HCl as dissolution medium.

Another embodiment relates to pharmaceutical compositions comprisingamorphous solid dispersions of nilotinib fumarate or nilotinib tartratefor oral administration, wherein at least 30% of nilotinib fumarate ornilotinib tartrate is released within 60 minutes in 0.01 M HCl media, asdetermined using USP dissolution apparatus II (paddle) at 75 rpm in 500mL of 0.01 M HCl media for 60 minutes followed by 900 mL of pH 5.0±0.05FeSSIF media buffer and FaSSIF media buffer for 90 minutes at 37±0.5° C.

In an embodiment, the obtained amorphous solid dispersions of nilotinibfumarate or nilotinib tartrate are combined with other pharmaceuticallyacceptable excipients such as diluents, binders, disintegrating agents,glidants, lubricants, plasticizers, colorants and surfactants to make itinto finished dosage form. The pharmaceutical compositions comprisinginventive amorphous solid dispersions of nilotinib fumarate or nilotinibtartrate and pharmaceutically acceptable excipients are prepared byusing process such as wet granulation, dry granulation, directcompression, preferably dry granulation. The dry granulation process maybe carried out either by direct compaction or roller compaction or both.

The pharmaceutical compositions comprising amorphous solid dispersionsof nilotinib or its pharmaceutically acceptable salts thereof andpharmaceutically acceptable excipients can be prepared by using directcompaction dry granulation, which process comprises of compressingmixture of the amorphous solid dispersions of nilotinib andintra-granular excipients into slug; compressed slugs are milled andpassed through mess screen manually or automatically. The resultinggranules are mixed with extra-granular excipients. This final mixture iseither compressed into tablet or filled in capsules.

The pharmaceutical compositions comprising amorphous solid dispersionsof nilotinib fumarate or nilotinib tartrate and pharmaceuticallyacceptable excipients may also be prepared by using roller compactiondry granulation, which process comprises of passing mixture of soliddispersion and intra-granular excipients between two high-pressurerollers to form consolidated and densified material; the resultantdensified material is then reduced to a uniform granule size by milling,which are then mixed with extra-granular excipients. This final mixtureis either compressed into tablet or filled in capsules.

The pharmaceutical compositions comprising amorphous solid dispersionsof nilotinib fumarate or nilotinib tartrate and pharmaceuticallyacceptable excipients may also be prepared by using direct compression,which process comprises of mixing the amorphous solid dispersions ofnilotinib fumarate or nilotinib tartrate and pharmaceutically acceptableexcipients; the resultant mixture is either compressed into tablets orfilled in capsules.

The pharmaceutical compositions comprising amorphous solid dispersionsof nilotinib fumarate or nilotinib tartrate and pharmaceuticallyacceptable excipients can also be prepared by wet granulation, whichprocess comprises of: (a) mixing amorphous solid dispersions ofnilotinib fumarate or nilotinib tartrate and pharmaceutically acceptableexcipients (b) adding sufficient solvent, wherein the solvent isselected form water, isopropanol, ethanol, to the mixture obtained fromstep (a) under shear to generate granules; (c) milling or grinding thegranules followed by sieving of said granules; optionally mixing withother excipients. This final mixture is either compressed into tablet orfilled in capsules.

The pharmaceutical composition of the present invention is preferably agranulate/particulate material. The granules/particles may be filledinto a capsule or compressed into a tablet. The tablet may optionally becoated with an additional enteric polymer or an immediate-releasecoating.

Moreover, the extrudates/granules of the present invention may beformulated into any suitable dosage form, including but not limited tooral suspensions, gels, tablets, capsules, immediate releaseformulations, delayed release formulations, controlled releaseformulations, extended release formulations, pulsatile releaseformulations, and mixed immediate and controlled release formulations.

Other pharmaceutically acceptable excipients may include, but are notlimited to, diluents, binders, disintegrating agents, surfactants,plasticizers, lubricants, glidants, chelating agents, coating agents andthe like or mixtures thereof as extra-granular agents.

Suitable diluents include microcrystalline cellulose, calcium carbonate,calcium phosphate-dibasic, calcium phosphate-tribasic, calcium sulfate,cellulose powdered, dextrates, dextrins, dextrose excipients, fructose,kaolin, lactitol, lactose, mannitol, sorbitol, starch, starchpregelatinized, sucrose, sugar compressible, sugar confectioners and thelike.

In an embodiment, diluent is included either in intra-granular portionor extra-granular portion or both. The diluent concentration ranges fromabout 10% to about 60% w/w of total composition. The diluentconcentration in the intra-granular portion ranges from about 10% toabout 60% w/w of total composition, preferably about 25% to about 35%.

Suitable binders include methyl cellulose, hydroxypropyl cellulose,hydroxypropyl methylcellulose, polyvinyl pyrrolidone, microcrystallinecellulose, gelatin, gum arabic, ethyl cellulose, polyvinyl alcohol,pullulan, pregelatinized starch, agar, tragacanth, sodium alginate,propylene glycol and the like. The concentration of binder ranges fromabout 1% to about 20% w/w of total composition, preferably about 10% toabout 15% w/w.

Suitable disintegrating agents include croscarmellose sodium,low-substituted hydroxypropyl cellulose (L-HPC), sodium starchglycollate, carboxymethyl cellulose, calcium carboxymethyl cellulose,sodium carboxymethyl cellulose, starch, crystalline cellulose,hydroxypropyl starch, pregelatinized starch, and the like and mixturesthereof. The concentration of disintegrating agent ranges from about 1%to about 10% w/w of total composition.

Suitable lubricants/glidants include colloidal silicon dioxide(AEROSIL®), stearic acid, magnesium stearate, calcium stearate, talc,hydrogenated castor oil, sucrose esters of fatty acid, microcrystallinewax, yellow beeswax, white beeswax, and the like and mixtures thereof.The concentration of lubricant/glidant ranges from about 0.5% to about5% w/w of total composition.

Suitable surfactants include both non-ionic and ionic (cationic, anionicand zwitterionic) surfactants suitable for use in pharmaceutical dosageforms. These include polyethoxylated fatty acids and its derivatives,for example, polyethylene glycol 400 distearate, polyethylene glycol-20dioleate, polyethylene glycol 4-150 mono dilaurate, and polyethyleneglycol—20 glyceryl stearate; alcohol—oil transesterification products,for example, polyethylene glycol—6 corn oil; polyglycerized fatty acids,for example, polyglyceryl—6 pentaoleate; propylene glycol fatty acidesters, for example, propylene glycol monocaprylate; mono anddiglycerides, for example, glyceryl ricinoleate; sterol and sterolderivatives; sorbitan fatty acid esters and its derivatives, forexample, polyethylene glycol—20 sorbitan monooleate and sorbitanmonolaurate; polyethylene glycol alkyl ether or phenols, for example,polyethylene glycol—20 cetyl ether and polyethylene glycol—10-100 nonylphenol; sugar esters, for example, sucrose monopalmitate;polyoxyethylene-polyoxypropylene block copolymers known as “poloxamer;”ionic surfactants, for example, sodium caproate, sodium glycocholate,soy lecithin, sodium stearyl fumarate, propylene glycol alginate, octylsulfosuccinate disodium, and palmitoyl carnitine; and the like andmixtures thereof. The concentration of surfactant ranges from about 0.5%to about 10% w/w of total composition.

Suitable plasticizers include polyethylene glycol, propylene glycol,polyethylene oxide, 1,2-butylene glycol, 2,3-butylene glycol, styreneglycol, diethylene glycol, triethylene glycol, tetraethylene glycol andmonoisopropyl ether, propylene glycol monoethyl ether, ethylene glycolmonoethyl ether, diethylene glycol monoethyl ether, sorbitol lactate,ethyl lactate, butyl lactate, ethyl glycolate, triethyl citrate, acetyltriethyl citrate, tributyl citrate and allyl glycolate. Theconcentration of plasticizer ranges from about 0.5% to about 10% w/w oftotal composition.

Suitable colouring agent include dyes and pigments such as iron oxidered or yellow, titanium dioxide, talc. The concentration of colouringagent ranges from about 0.1% to about 1% w/w of total composition.

Suitable chelating agents include, one or more of, but not limited toethylenediaminetetraacetic acid (EDTA), disodium EDTA and derivativesthereof, citric acid and derivatives thereof, niacinamide andderivatives thereof, and sodium desoxycholate and the like or mixturesthereof. The concentration of chelating agent ranges from about 0.1% toabout 1% w/w of total composition.

The pharmaceutical composition, may also optionally be coated, i.e.,seal coated and/or enteric coated and/or film coated. Preferably, thepharmaceutical composition may be seal coated and finally film coated orit may be seal coated and further enteric coated. Optionally,pharmaceutical compositions of the invention may be film coated.Preferably, the film coating polymer may be present in an amount fromabout 2 to 10% w/w.

In an embodiment, the invention relates to pharmaceutical compositionscomprising amorphous solid dispersions of nilotinib fumarate ornilotinib tartrate for oral administration, which solid dispersioncomprises at least one pharmaceutically acceptable carrier andoptionally at least one organic acid, having a fed/fasted ratio of0.8-1.5 for AUC and/or C_(max).

Another embodiment relates to pharmaceutical compositions comprisingamorphous solid dispersions of nilotinib fumarate or nilotinib tartratefor oral administration, which solid dispersion comprises at least onepharmaceutically acceptable carrier and optionally at least one organicacid, having a fasted state bioavailability that exceeds 130% of thecommercially available product.

In yet another embodiment, the invention relates to a kit comprising a)a solid dosage form comprising an effective amount of amorphous soliddispersions of nilotinib fumarate or nilotinib tartrate and apharmaceutically acceptable carrier, and b) instructions for oraladministration of the dosage form (a), which i) do not specifyadministration with food, or ii) indicate that the dosage form (a) maybe administered without regard to food.

Certain embodiments relate to pharmaceuticals compositions as describedherein, which are stable, e.g., stable over the shelf life of the drugproduct. As used herein, the term “stable” is defined as no more thanabout 5% loss of nilotinib under typical commercial storage conditions.In certain embodiments, the formulations of the present invention willhave no more than about 3% loss of nilotinib, more preferably, no morethan about 2% loss of nilotinib, under typical commercial storageconditions. The composition retains at least about 95% of the potency ofnilotinib after storing the composition at 40° C. and 75% relativehumidity for at least three months. In certain aspects, the term“stable” refers to chemical stability, wherein not more than 1.5% w/w oftotal related substances are formed on storage at accelerated conditionsof stability at 40° C. and 75% relative humidity or at 25° C. and 60%relative humidity for a period of at least three months or to the extentnecessary for use of the composition.

Dosage and Administration

The dose of the therapeutic compound will be in the range from about 0.1to about 1000 mg per kilogram body weight of the recipient per day.Exemplary unit doses of therapeutic compound range from 20 mg to 1000mg, including unit dosages of 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 350 mg, 400 mg, 450mg, 500 mg, 550 mg, 600 mg and 800 mg. Alternatively lower doses may begiven, for example doses of 0.5 to 100 mg; 0.5 to 50 mg; or 0.5 to 20 mgper kilogram body weight per day. The effective dosage range of thepharmaceutically acceptable salts may be calculated based on the weightof the active moiety to be delivered. If the salt exhibits activityitself, the effective dosage may be estimated as above using the weightof the salt, or by other means known to those skilled in the art.

Methods of Treatment

The invention provides methods of therapeutically treating proliferativedisorders by administering a quantity of: a composition of theinvention; formulation comprising a composition of the invention; ordosage form comprising a composition of the invention, whichadministered quantity provides from about 25 mg to about 500 mg ofnilotinib per day, either in a single or divided dose. In someembodiments it is preferred to administer daily, in either a single ordivided dose an amount of: a composition of the invention or dosage formcomprising a composition of the invention which provides from about 50mg to about 400 mg of nilotinib, preferably at least about 50 mg, 150 mgand 200 mg of nilotinib. In some embodiments it is preferred to providetreatment by administering from about 300 mg of nilotinib to about 400mg of nilotinib per day.

The pharmaceutical composition according to the present inventionimproves the absorption behavior of nilotinib in human body, andincreases the absorption and bioavailability of the drug in comparisonto the commercially available nilotinib formulation (TASIGNA®).

In certain embodiments, the dose of nilotinib is at the most about 98%w/w, or at the most about 95% w/w, or at the most about 90% w/w, or atthe most about 85% w/w, or at the most about 80% w/w, or at the mostabout 75% w/w, or at the most about 70% w/w, or at the most about 65%w/w, or at the most about 60% w/w, or at the most about 55% w/w or atthe most about 50% w/w of the dose of the nilotinib administered in theform of a commercially available product.

In an embodiment, the invention relates to a method for treating aproliferative disorder in a human, which method comprises administeringa) a solid dosage form comprising an effective amount of amorphous soliddispersions of nilotinib fumarate or nilotinib tartrate and apharmaceutically acceptable carrier; and b) instructions for oraladministration of the dosage form (a), which i) do not specifyadministration with food, or ii) indicate that the dosage form (a) maybe administered without regard to food.

As used herein, “to treat” a condition or “treatment” of the conditionis an approach for obtaining beneficial or desired results, such asclinical results. Beneficial or desired results can include, but are notlimited to, alleviation or amelioration of one or more symptoms orconditions; diminishment of extent of disease, disorder, or condition;stabilized (i.e., not worsening) state of disease, disorder, orcondition; preventing spread of disease, disorder, or condition; delayor slowing the progress of the disease, disorder, or condition;amelioration or palliation of the disease, disorder, or condition; andremission (whether partial or total), whether detectable orundetectable. “Palliating” a disease, disorder, or condition means thatthe extent and/or undesirable clinical manifestations of the disease,disorder, or condition are lessened and/or time course of theprogression is slowed or lengthened, as compared to the extent or timecourse in the absence of treatment.

For administration to animal or human subjects, the pharmaceuticalcompositions comprise an effective dosage amount of nilotinib or apharmaceutically acceptable salt thereof. The formulation may beprepared using conventional methods, for example, depending on thesubject to be treated, the mode of administration, and the type oftreatment desired (e.g., prevention, prophylaxis, or therapy).

The nilotinib or pharmaceutically acceptable salt thereof, may bepresent in amounts totaling 1-95% by weight of the total weight of thecomposition.

Preferably, the pharmaceutical composition will be provided in a dosageform that is suitable for oral administration, including but not limitedto hard capsules (e.g., hard gelatin capsules or hard hydroxypropylmethylcellulose capsules), soft gelatin capsules, tablets, caplets,enteric coated tablets, chewable tablets, enteric coated hard gelatincapsules, enteric coated soft gelatin capsules, lozenges, films, strips,suspensions, syrups, or sprinkles. The compositions may be formulatedaccording to conventional pharmaceutical practice.

The dosage levels can be dependent on the nature of the condition, drugefficacy, the condition of the patient, the judgment of thepractitioner, and the frequency and mode of administration. The unitdosage forms can be administered to achieve any daily amount describedherein, such as by administering one to five times daily (e.g., one,two, three, four, or five times daily).

In an aspect, the invention relates to certain methods of treatmentcomprising administration of a pharmaceutical composition describedherein, where the total daily dosage amount is 400 mg, 600 mg or 800 mg.

Preferred unit dosage amounts include 15 mg, 20 mg, 25 mg, 30 mg, 35 mg,40 mg, 45 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, or 200 mg ofnilotinib or a pharmaceutically acceptable salt thereof.

The term “unit dosage form” refers to a physically discrete unitsuitable as a unitary dosage, such as a tablet, caplet, hard capsule, orsoft capsule, each unit containing a predetermined quantity of a drug.

By “effective” amount is meant the amount of a drug sufficient to treat,prevent, or ameliorate a condition in a subject or patient. Theeffective amount of nilotinib or pharmaceutically acceptable saltthereof, used to practice the present invention for therapeuticmanagement of a condition may be determined and adjusted by a person ofordinary skill to provide the appropriate amount and dosage regimen,e.g., depending upon one or more of the manner of administration, theage, body weight, sex, and/or general health of the patient.

Dissolution Testing

In an embodiment, amorphous solid dispersions of nilotinib fumarate ornilotinib tartrate and pharmaceutical compositions manufactured in thepresent application were tested for comparative dissolution by using USPapparatus-II (paddle) in 0.01 M HCl followed by buffer (FaSSIF and/orFeSSIF) media. Preparation of dissolution media required for the studieswas prepared as described below.

Preparation of 0.01 M HCl (3.5 L):

2.9 mL of 37% HCl was added into 3.5 L purified water

Preparation of Double Strength FaSSIF (3 L):

To 3 liters of purified water was added: 2.53 g sodium hydroxide, 23.7 gsodium dihydrogen phosphate monohydrate, and 37.1 g sodium chloride,followed by mixing thoroughly. Once mixed, the pH was adjusted to6.50±0.05 with sodium hydroxide or hydrochloric acid. Once the pH wasadjusted, 13.6 g FaSSIF powder was added and mixed thoroughly.

Preparation of Double Strength FeSSIF (2.5 L)

To 2.5 liters of purified water was added: 20.2 g sodium hydroxide, 43.3g glacial acetic acid, and 59.4 g sodium chloride, followed by mixingthoroughly. Once mixed, the pH was adjusted to 5.0±0.05 with sodiumhydroxide or acetic acid. Once the pH was adjusted, 56.0 g FaSSIF powderwas added and mixed thoroughly.

The samples withdrawn from the dissolution study were analyzed for drugcontent using the following HPLC procedure. The materials and generalconditions are listed below:

TABLE 1 Chromatographic conditions Chromatographic Isocratic 35:65(Mobile phase A): Mode (Mobile phase B) Column YMC Pack Pro C18, 150 mm× 4.6 mm, 3 μm Wavelength 230 nm Flow rate 1.2 mL/min Injection volume 5μL Column temperature 45° C. Run time 6 minutes Mobile Phase A 1.36 g ofPotassium dihydrogen phosphate and 1 g of 1-octane sulphonic acid sodiumsalt to 1 litre of water and stir to dissolve. Mobile Phase B To 850 mLof Acetonitrile, add 100 mL of Methanol and 50 mL of water and mixthoroughly.

EXAMPLES

The following examples are exemplary and not intended to be limiting.The above disclosure provides many different embodiments forimplementing the features of the invention, and the following examplesdescribe certain embodiments. It will be appreciated that othermodifications and methods known to one of ordinary skill in the art canalso be applied to the following experimental procedures, withoutdeparting from the scope of the invention.

Example 1

Solid dispersions of nilotinib base having compositions set forth inTable 2 were prepared by spray drying.

TABLE 2 Composition 1 2 3 4 5 Ingredients % w/w % w/w % w/w % w/w % w/wNilotinib base 33.3 25 20 33.3 25 HPMC-AS 66.6 75 80 — — HPMCP 55 — — —66.6 75 DCM:Methanol (3:1) q.s. q.s. q.s. q.s. q.s. q.s.: quantitysufficient

Manufacturing Procedure:

The required quantities of nilotinib base and the selected carrier(i.e., HPMC-AS and HPMCP 55) according to Table 2, were dissolved in amixture of dichloromethane (DCM) and methanol in 3:1 ratio, to provide afeeder solution. The obtained feeder solution was passed through anozzle as a fine spray into a chamber where the solvent was evaporatedquickly to generate particles containing the nilotinib and carrier. Theresulting spray dried powder was dried further to remove residualsolvents in a static dryer. Powder X-ray diffraction patterns ofnilotinib base solid dispersion of composition 2 and 5 were provided inFIG. 1 . The total weight of each composition was 100 grams.

Example 2

Solid dispersions of nilotinib fumarate having the compositions setforth in Table 3 were prepared by spray drying.

TABLE 3 Composition 6 7 8 9 10 11 12 Ingredients % w/w % w/w % w/w % w/w% w/w % w/w % w/w Nilotinib fumarate 33.3 25 20 33.3 25 33.3 25 HPMC-AS66.6 75 80 — — — — PVP K30 — — — 66.6 75 — — HPMC E3 — — — — — 66.6 75Methanol q.s. q.s. q.s. q.s. q.s. q.s. q.s. Dichloromethane — — — q.s.q.s. q.s. q.s. q.s.: quantity sufficient

Manufacturing Procedure:

The required quantities of nilotinib fumarate and carrier (i.e.,HPMC-AS, PVP K30 or HPMC E3), according to Table 3 were dissolved inmethanol and/or dichloromethane, to provide feeder solutions. Theobtained feeder solutions were passed through nozzles as fine spray intochambers where the solvents (i.e., methanol and dichloromethane) wereevaporated quickly to generate powders. The resulting spray driedpowders were further dried to remove residual solvents in a staticdryer. The total weight of each prepared composition was 100 grams.

Example 3

Solid dispersions of nilotinib fumarate having the compositions setforth in Table 4 were prepared by spray drying.

TABLE 4 Composition 13 14 15 Ingredients Qty(g) % w/w Qty(g) % w/wQty(g) % w/w Nilotinib fumarate 4.13 20.6 4.13 20.6 4.13 20.6 HPMC-AS12.45 62.3 — — — — PVP K30 — — 12.45 62.3 — — HPMC E3 — — — — 12.45 62.3Fumaric acid 3.41 17.1 3.41 17.1 3.41 17.1 Methanol q.s. q.s. q.s. q.s.q.s. q.s. Dichloromethane — — q.s. q.s. q.s. q.s. q.s.: quantitysufficient

Manufacturing Procedure:

The required quantities of nilotinib fumarate, HPMC-AS, PVP K30, HPMC E3and fumaric acid as mentioned in Table 4 were dissolved in methanol, toprovide feeder solutions. The obtained feeder solutions were passedthrough nozzles as fine spray into chambers where solvents (i.e.,methanol and dichloromethane) were evaporated quickly to generatepowders. The obtained spray dried powders were dried further to removeresidual solvents in a static dryer. Total weight of each composition is20 grams.

The powder X-ray diffraction pattern (PXRD) for the amorphous soliddispersion of nilotinib fumarate of Composition 13 is illustrated inFIG. 2 .

Example 4

Solid dispersions of nilotinib tartrate having composition set forth inTable 5 were prepared by spray drying.

TABLE 5 Composition 16 17 Ingredients Qty(g) % w/w Qty(g) % w/wNilotinib tartrate 25 25 20.4 20.4 HPMC-AS 75 75 63.7 63.7 Tartaric acid— — 15.9 15.9 Methanol q.s. q.s. q.s. q.s.

Manufacturing Procedure:

The required quantities of nilotinib tartrate, HPMC-AS and tartaric acidas mentioned in Table 5 were dissolved in methanol to prepare feedersolutions. The obtained feeder solutions were passed through nozzles asfine spray into chambers where methanol was evaporated quickly togenerate powders. The resulting spray dried powders were dried furtherto remove residual solvent in a static dryer. Total weight of eachprepared composition was 100 grams.

Powder X-ray diffraction pattern of Composition 16 is illustrated inFIG. 3 . Instrument used for spray drying in the above examples 1-4 wasBuchi B-290 mini-spray dryer and parameters of spray drying were givenbelow:

-   -   Total dissolved solids: 10% w/v    -   Inlet Temperature(° C.): 120    -   Aspirator rate: 100%    -   Nozzle type: twin fluid nozzle    -   Nozzle pressure: 50 psi    -   Feed rate: 10 mL min⁻¹

Example 5

Solid dispersions of nilotinib tartrate having the compositions setforth in Table 6 were prepared by hot-melt extrusion (HME).

TABLE 6 Composition 18 19 20 21 22 23 24 Ingredients % w/w % w/w % w/w %w/w % w/w % w/w % w/w Nilotinib tartrate 33.3 25 20 33.3 25 33.3 25HPMC-AS 66.6 75 80 — — — — HPMC E3 — — — 66.6 75 — — PVP K30 — — — — —66.6 75

Manufacturing Procedure:

The required quantities of nilotinib tartrate, HPMC-AS, HPMC E3 and PVPK30 were weighed as mentioned in the Table 6 and physically mixed in apolybag. The resultant mixtures were then placed in an extruder hopperseparately. The mixtures were passed through the heated extruder at atemperature range from about 30° C. to about 170° C., as determined bytemperature setting of the extruder heating zones so that melting orsoftening of the carrier occurred. The resulting extrudate was cooled toroom temperature and milled, then the milled material was sifted througha 30-mesh screen. Total weight of each prepared composition was 100grams.

Example 6

Solid dispersions of nilotinib tartrate having compositions set forth inTable 7 were prepared by hot melt extrusion (HME).

TABLE 7 Composition 25 26 27 28 29 30 31 32 33 Ingredients % w/wNilotinib tartrate 26.4 20.4 17.3 20.5 17.0 20.5 17.0 20.5 17.0 HPMC-AS52.9 63.7 69.2 61.5 68.0 61.5 68.0 61.5 68.0 Tartaric acid 20.7 15.913.5 16.0 13.3 16.0 13.3 16.0 13.3 Triethyl citrate (TEC) — — — 2.051.69 — — — — Polyethylene glycol — — — — — 2.05 1.69 — — (PEG) Propyleneglycol — — — — — — — 2.05 1.69

Manufacturing Procedure:

The required quantities of nilotinib tartrate, HPMC-AS, triethyl citrate(TEC), polyethylene glycol (PEG), propylene glycol (PG) and tartaricacid were weighed as mentioned in the Table 7 and physically mixed in apolybag. The resultant mixtures were then placed in an extruder hopperseparately, and were passed through heated extruder at a temperaturerange from about 30° C. to about 170° C., as determined by temperaturesetting of the extruder heating zones so that melting or softening ofthe carrier occurred. The resulting extrudate was cooled to roomtemperature and milled, then the milled material was sifted through a30-mesh screen. Total weight of each prepared composition was 100 grams.

The Thermofischer11 extruder used in the examples 5 and 6 has a singlescrew solid conveying mechanism that extends from the hopper throughmultiple heating zones to the extrusion die. Temperature controls,extruder screw speed, feed rate and the process parameters used duringhot-melt extrusion are provided in

TABLE 8 Zone Temperature Zone 1 33-35° C. Zone 2 60° C. Zone 3 120° C.Zone 4 130° C. Zone 5 140° C. Zone 6 150° C. Zone 7 160° C. Zone 8 170°C. Parameters Die 2 mm Screw speed 100 rpm Feed rate 1 g/minute

Example 7

Nilotinib capsules were prepared, having the compositions set forth inTable 9.

TABLE 9 Composition 34 Composition 35 Ingredients mg/unit % w/w mg/unit% w/w Nilotinib base (solid dispersion 200 68 — — from composition 2)Nilotinib base (solid dispersion — — 200 68 from composition 5)Intra-granular material Microcrystalline cellulose 73.4 25.0 73.4 25.0Croscarmellose Sodium 14.6 5.0 14.6 5.0 AEROSIL ® 1.5 0.5 1.5 0.5Magnesium stearate 1.5 0.5 1.5 0.5 Extra-granular material AEROSIL ® 1.50.5 1.5 0.5 Magnesium stearate 1.5 0.5 1.5 0.5 Total 294 100.1 294 100.1

Manufacturing Procedure:

-   -   1. The required quantities of nilotinib base solid dispersion        (from composition 2 or 5) were mixed with intragranular        ingredients (i.e., microcrystalline cellulose, croscarmellose        sodium, AEROSIL® and magnesium stearate) as mentioned in Table        9.    -   2. Mixtures obtained were compacted with roller compactor        separately. These compacts were milled and passed through a        30-mesh screen to obtain granules, which were blended with        AEROSIL® to obtain pre-lubricated blends.    -   3. Pre-lubricated blends were lubricated with magnesium        stearate.    -   4. Final blends were filled into capsules with respective fill        weights for respective strengths of 25 mg to 100 mg.

Dissolution Profiles of Composition 34 and 35 in 0.01 M HCl Acid Mediaand Followed by FeSSIF Media of pH 5.0±0.05.

When tested by using USP apparatus II (paddle); 500 mL of 0.01 M HClmedia for 60 minutes and followed by 900 mL of pH 5.0±0.05 FeSSIF mediafor 90 minutes at 37±0.5° C. and stirred at 75 rpm, the dissolutionprofile of Composition 34 and 35 were compared with TASIGNA® 50 mgcapsule in following Table 10. Samples of 5 mL were withdrawn at 15, 30and 60 minutes in 0.01 M HCl acid media and 65, 70, 75, 90, 105, 120,150 and 180-minute time points in FeSSIF media. Withdrawn samples werefiltered with 0.45 μm nylon membrane filter and then diluted withdimethyl sulfoxide (DMSO) in 1:1 ratio and analysed using HPLC systemwith UV spectrophotometer at a wavelength 230 nm. The results of themeasurements are given in Table 10 and shown graphically in FIG. 4 .

TABLE 10 % of Drug released TASIGNA ® Dissolution Time 50 mg CompositionComposition Media (minutes) Capsule 34 35 0.01M HCl 0 0 0 0 acid media15 28 24 3 30 58 27 4 60 76 33 3 FeSSIF 65 24 43 12 media 70 19 42 14 7517 40 10 90 19 40 11 105 17 37 12 120 17 36 10 150 18 33 10 180 18 33 —

Example 8

Nilotinib fumarate capsules were prepared, having the compositions setforth in Table 11.

TABLE 11 Composition 36 37 38 39 40 41 42 Ingredients mg/unit Nilotinibfumarate (solid 293 263.8 205.2 146.5 263.8 205.2 146.5 dispersion fromcomposition 13) Nilotinib fumarate (solid — 29.3 87.9 146.5 — — —dispersion from composition 14) nilotinib fumarate (solid — — — — 29.387.9 146.5 dispersion from composition 15) Intra-granular materialMicrocrystalline 107.5 107.5 107.5 107.5 107.5 107.5 107.5 celluloseCroscarmellose Sodium 21.4 21.4 21.4 21.4 21.4 21.4 21.4 AEROSIL ® 2.152.15 2.15 2.15 2.15 2.15 2.15 Magnesium stearate 2.15 2.15 2.15 2.152.15 2.15 2.15 Extra-granular material AEROSIL ® 2.15 2.15 2.15 2.152.15 2.15 2.15 Magnesium stearate 2.15 2.15 2.15 2.15 2.15 2.15 2.15Total 430.7 430.7 430.7 430.7 430.7 430.7 430.7

Manufacturing Procedure:

-   -   1. The required quantities of nilotinib fumarate solid        dispersion of Composition 13, 14 and 15 were weighed and mixed        with intragranular ingredients (i.e., microcrystalline        cellulose, croscarmellose sodium, AEROSIL® and magnesium        stearate) as mentioned in Table 11.    -   2. Mixtures obtained were compacted with roller compactor        separately, these compacts were milled and passed through a        30-mesh screen separately to obtain granules, which were blended        with AEROSIL® to obtain pre-lubricated blends.    -   3. Pre-lubricated blends were lubricated with magnesium        stearate.    -   4. Final blends were filled into capsules with respective fill        weights for respective strengths of 25 mg to 100 mg.

Dissolution Profile of Composition 36 and TASIGNA® 50 mg Capsule in 0.01M HI Media Followed by FaSSIF or FeSSIF Media.

When TASIGNA® 50 mg capsule and Composition 36 are tested by using USPapparatus II (paddle); 500 mL of 0.01 M H22 media for 60 minutes andfollowed by 900 mL of FeSSIF media and FaSSIF media for 90 minutes at37±0.5 00 and stirred at 75 rpm, the dissolution profile of Composition36 was compared with TASIGNA® 50 mg capsule in FeSSIF and FaSSIF mediain following Table 12. Samples of 5 mL were withdrawn at 15, 30 and 60minutes in 0.01 M HCl acid media and 65, 70, 75, 90, 105, 120, 150 and180-minute time points in FeSSIF and FaSSIF media. Withdrawn sampleswere filtered with 0.45 μm nylon membrane filter and then diluted withdimethyl sulfoxide (DMSO) in 1:1 ratio and analysed using HPLC systemwith UV spectrophotometer at a wavelength 230 nm. The results of themeasurements are given in Table 12 and shown graphically in FIG. 5 .

TABLE 12 FaSSIF buffer media FeSSIF buffer media TASIGNA ® Compo-TASIGNA ® Compo- Dissolution Time in 50 mg sition 50 mg sition mediaminutes Capsule 36 Capsule 36 0.01M HCl 0 0 0 0 0 acid media 15 19 19 2822 30 56 — 58 — 60 74 40 76 43 Buffer 65 3 — 24 — media 70 2 30 19 36 752 30 17 31 90 1 28 19 29 105 3 28 17 29 120 2 27 17 31 150 2 26 18 31180 2 26 18 32

Example 9

Solid dispersions of nilotinib fumarate were prepared, having thecompositions set forth in Table 13

TABLE 13 Composition 43 44 45 46 47 48 49 Ingredients mg/unit Nilotinibfumarate (solid 243.0 218.7 170.2 121.5 218.7 170.2 121.5 dispersionfrom composition 7) Nilotinib fumarate (solid — 24.3 72.9 121.5 — — —dispersion from composition 10) Nilotinib fumarate (solid — — — — 24.372.9 121.5 dispersion from composition 12) Microcrystalline cellulose89.2 89.2 89.2 89.2 89.2 89.2 89.2 Croscarmellose Sodium 17.7 17.7 17.717.7 17.7 17.7 17.7 AEROSIL ® 1.8 1.8 1.8 1.8 1.8 1.8 1.8 Magnesiumstearate 1.8 1.8 1.8 1.8 1.8 1.8 1.8 Extra-granular material AEROSIL ®1.8 1.8 1.8 1.8 1.8 1.8 1.8 Magnesium stearate 1.8 1.8 1.8 1.8 1.8 1.81.8 Total 357.2 357.2 357.2 357.2 357.2 357.2 357.2

The manufacturing procedure was as follows:

-   -   1. The required quantities of nilotinib fumarate solid        dispersion of Composition 7, 10 and 12 were weighed and mixed        with intragranular ingredients (i.e., microcrystalline        cellulose, croscarmellose sodium, AEROSIL® and magnesium        stearate) as mentioned in Table 13.    -   2. Mixtures obtained were compacted with roller compactor        separately, these compacts were milled and passed through a        30-mesh screen separately. The obtained granules were blended        with AEROSIL® to obtain pre-lubricated blends.    -   3. Pre-lubricated blends were lubricated with magnesium        stearate.    -   4. Final blends were filled into capsules with respective fill        weights for respective strengths of 25 mg to 100 mg.

Example 10

Nilotinib tartrate capsules were prepared, having the compositions setforth in Table 14.

TABLE 14 Composition 50 Composition 51 Ingredients mg/unit % w/w mg/unit% w/w Nilotinib tartrate (solid dispersion 256 68.0 — — from composition16) Nilotinib tartrate (solid dispersion — — 306 68.0 from composition17) Intra-granular Material Microcrystalline cellulose 78.55 25.0 93.925.0 Croscarmellose Sodium 15.64 5.0 18.65 5.0 AEROSIL ® 1.58 0.5 1.880.5 Magnesium stearate 1.58 0.5 1.88 0.5 Extra-granular MaterialAEROSIL ® 1.58 0.5 1.88 0.5 Magnesium stearate 1.58 0.5 1.88 0.5 Total356.48 100 426.07 100

Manufacturing Procedure:

The required quantities of nilotinib tartrate solid dispersion ofComposition 16 and 17 were weighed according to Table 14, mixed withintragranular ingredients (i.e., microcrystalline cellulose,croscarmellose sodium, AEROSIL® and magnesium stearate) according toTable 14. The resulting mixtures obtained were each separately compactedwith roller compactor. The resulting compacts were each separatelymilled and passed through a 30-mesh screen. The obtained granules wereblended with AEROSIL® to obtain pre-lubricated blends. Thepre-lubricated blends were lubricated with magnesium stearate. The finalblends were filled into capsules with respective fill weights forrespective strengths of 25 mg to 100 mg.

Dissolution Profiles of Composition 50 and 51 in 0.01 M HCl Acid Mediaand Followed by FeSSIF Media of pH 5.0±0.05.

When tested by using USP apparatus II (paddle); 500 mL of 0.01 M HClmedia for 60 minutes and followed by 900 mL of pH 5.0±0.05 FeSSIF mediafor 90 minutes at 37±0.5° C. and stirred at 75 rpm, the dissolutionprofiles of composition 50 and 51 were compared with TASIGNA® 50 mgcapsule in following Table 15. Samples of 5 mL were withdrawn at 15, 30and 60 minutes in 0.01 M HCl acid media and 65, 70, 75, 90, 105, 120,150 and 180-minute time points in FeSSIF media. Withdrawn samples werefiltered with 0.45 μm nylon membrane filter and then diluted withdimethyl sulfoxide (DMSO) in 1:1 ratio and analysed using HPLC systemwith UV spectrophotometer at a wavelength 230 nm. The results of themeasurements are given in Table 15 and shown graphically in FIG. 6 .

TABLE 15 % of Drug released TASIGNA ® Dissolution Time 50 mg CompositionComposition Media (minutes) Capsule 50 51 0.01M HCl 0 0 0 0 acid media15 28 22 43 30 58 — — 60 76 45 74 FeSSIF 65 24 — — buffer media 70 19 3654 75 17 36 52 90 19 37 50 105 17 34 51 120 17 34 52 150 18 36 52 180 1836 51

Example 11

Solid dispersion of nilotinib tartrate was prepared, having thecomposition set forth in Table 16

TABLE 16 Composition 52 Ingredients mg/unit % w/w Nilotinib tartrate 6419.9 HPMC-AS MF 200 62.1 Tartaric acid 50 15.5 AEROSIL ® 5 1.6 Magnesiumstearate 3 0.9 Total 322 100

Manufacturing Procedure:

The required quantities of nilotinib tartrate, HPMC-AS MF and tartaricacid were weighed and blended for 5 minutes to obtain a premix,according to Table 16. The premix obtained was subjected to hot-meltextrusion, which was performed on a hot melt extruder (Pharma 11Twin-screw Extruder) at screw speed of 100 rpm using feed rate of 1gram/minute. The extrude was collected at a temperature of 160° C.,milled and passed through 40-mesh screen to obtain granules. Thespecified quantity of AEROSIL® was co-sifted with granules through40-mesh screen and blended for 5 minutes to obtain pre-lubricated blend.Magnesium stearate was passed through 60-mesh screen and added topre-lubricated blend and lubricated for 5 minutes.

Dissolution Profile of TASIGNA® 50 mg Capsule and Composition 52 in 0.01M HCl Acid Media and Followed by Double Strength FaSSIF Media

When tested by using USP apparatus II (paddle); 500 mL of 0.01 M HClmedia for 60 minutes and followed by 900 mL of double strength FaSSIFmedia for 120 minutes at 37±0.5° C. and stirred at 75 rpm, thedissolution profile of Composition 52 was compared with TASIGNA® 50 mgcapsule in following Table 17. Samples of 5 mL were withdrawn at 15, 30and 60 minutes in 0.01 M HCl acid media and 65, 70, 75, 90, 105, 120,150 and 180-minute time points in FaSSIF media. Withdrawn samples werefiltered with 0.45 μm nylon membrane filter and then diluted withdimethyl sulfoxide (DMSO) in 1:1 ratio and analysed using HPLC systemwith UV spectrophotometer at a wavelength 230 nm. The results of themeasurements are given in Table 17 and shown graphically in FIG. 7 .

TABLE 17 % of Drug released TASIGNA ® Dissolution Time 50 mg CompositionMedia (minutes) Capsule 52 0.01M HCl acid 0 0 0 media 15 19 71 30 56 —60 74 80 65 3 — Double 70 2 10 strength 75 2 11 FaSSIF media 90 1 11 1053 — 120 2 11 150 2 11 180 2 —

Example 12

A study was conducted to test the pharmacokinetics and bioavailabilityof a Composition 52 in healthy adult, beagle dog subjects, with thesubjects in a fasted state.

This study is open label, balanced, non-randomized two-treatment,two-sequence, two-period, single-dose, two-way crossover oralbioequivalence study of Composition 52 and TASIGNA® 50 mg capsules wasconducted in 8 healthy, adult, beagle dogs under fasting conditions(n=8).

TABLE 18 Composition 52 (Fast)/ 90% Pharmacokinetic CompositionTASIGNA ® TASIGNA ® Confidence parameter 52 (Fast) (Fast) Fast) (%)interval (CI) C_(max)  783.4 ± 580.59 284.65 ± 138.9  255.48148.59-439.28 (ng/mL) AUC_(0-t) 2497.25 ± 1518.22 901.76 ± 464.53 274.18162.50-462.61 (ng · hr/mL) AUC_(0-∞) 2518.03 ± 1516.61 950.61 ± 465.20257.3 159.43-415.26 (ng · hr/mL)

Example 13

Nilotinib fumarate capsules were prepared, having the composition setforth in Table 19.

TABLE 19 Composition 53 Ingredients mg/capsule % w/w Nilotinib fumarate60.77 20.7 HPMC-AS MF 182.3 62.2 Fumaric acid 50 17.1 Methanol 9000 —Total weight of solid dispersion 293.07 100 filled in each capsule

Manufacturing Procedure:

The required quantities of nilotinib fumarate, fumaric acid and HPMC-ASwere dissolved in methanol solvent to prepare a solution containing 3%solid content. Prepared solution was sprayed on a spray dryer (BuchiB-290) at an inlet temperature of 115° C. and flow rate of 10 mL/minute.Obtained spray dried solid dispersion was filled into capsules.

Dissolution Profiles of TASIGNA® 50 mg Capsule and Composition 53 in0.01 M HCl Acid Media and Followed by pH 6.5 FaSSIF Buffer Media orFollowed by pH 5.0 FeSSIF Buffer Media

When tested by using USP apparatus II (paddle); 500 mL of 0.01 M HClmedia for 60 minutes and followed by 900 mL of pH 6.5 FaSSIF buffermedia or followed by pH 5.0 FeSSIF buffer media, each for 120 minutes at37±0.5° C. and stirred at 75 rpm, the dissolution profiles ofComposition 53 were compared with TASIGNA® 50 mg capsule in followingTable 20. Samples of 5 mL were withdrawn at 15, 30 and 60 minutes in0.01 M HCl acid media and 65, 70, 75, 90, 105, 120, 150 and 180-minutetime points in FaSSIF buffer media and FeSSIF buffer media. Withdrawnsamples were filtered with 0.45 μm nylon membrane filter and thendiluted with dimethyl sulfoxide (DMSO) in 1:1 ratio and analysed usingHPLC system with UV spectrophotometer at a wavelength 230 nm. Theresults of the measurements are given in Table 20 and shown graphicallyin FIG. 8 .

TABLE 20 % of Drug released FaSSIF buffer stage FeSSIF buffer stageTASIGNA ® TASIGNA ® Dissolution Time 50 mg Composition 50 mg CompositionMedia (min) Capsule 53 Capsule 53 0.01M HCl 0 0 0 0 0 acid media 15 1915 28 17 30 56 — 58 — 60 74 29 76 30 Buffer 65 3 — 24 — Stage 70 2 20 1927 75 2 19 17 27 90 1 19 19 27 105 3 21 17 29 120 2 23 17 28 150 2 21 1827 180 2 26 18 28

Example 14

A study was conducted to test the pharmacokinetics and bioavailabilityof a Composition 53 in 6 healthy adult beagle dog subjects, with thesubjects in a fasted state.

TABLE 21 Composition Composition 53 (Fast)/ 90% Pharmacokinetic 53TASIGNA ® TASIGNA ® Confidence parameter (Fast) (Fast) (Fast) (%)interval (CI) C_(max) 784.96 ± 1155.34  1142 ± 775.2 237.39106.66-528.34 (ng/mL) AUC_(0-t) 2042.7 ± 2406.51 2538.53 ± 1875.4 218.51 111.48-428.29 (ng · hr/mL) AUC_(0-∞) 2110.8 ± 2425.08 3871.25 ±2486.05 220.17 116.17-417.28 (ng · hr/mL)

Example 15

A nilotinib fumarate tablets were prepared, having the composition setforth in Table 22.

TABLE 22 Composition 54 Composition 55 Dry-granulation Wet granulationprocess process Ingredients mg/tablet % w/w mg/tablet % w/w Nilotinibfumarate solid 293.07 57.6 293.07 57.9 dispersion of Composition 53Intra-granular material Microcrystalline cellulose 100 19.6 100 19.8Crospovidone 50 9.8 — — AEROSIL ® 5 1.0 — — Magnesium stearate 3 0.6 — —METHOCEL ® E5 — — 5 1.0 Purified water — — q.s. — Extra-granularmaterial Crospovidone 50 9.8 100 19.8 AEROSIL ® 5 1.0 5 1.0 Magnesiumstearate 3 0.6 3 0.6 Total 509.07 100 506.07 100 Note: q.s.—quantitysufficient

Manufacturing Procedure

The dry-granulation/slugging process comprised the following:

-   -   1. The required quantities of nilotinib fumarate solid        dispersion of Composition 53, microcrystalline cellulose,        Crospovidone, AEROSIL© and magnesium stearate as mentioned in        Table 22 were weighed and blended for 5 minutes.    -   2. The obtained blend was compressed with 21.00 mm round punches        to make slugs.    -   3. The obtained slugs were milled and passed through 40-mesh        screen to obtain granules.    -   4. The required quantity of Crospovidone and AEROSIL® were        weighed and co-sifted with granules through 40-mesh screen and        blended for 5 minutes to obtain pre-lubricated blend.    -   5. Magnesium stearate was passed through 60-mesh screen and        added to pre-lubricated blend and lubricated for 5 minutes.

The wet-granulation process comprised the following:

-   -   1. Nilotinib fumarate solid dispersion of Composition 53 was        granulated with aqueous solution of METHOCEL® E5 in a rapid        mixer granulator. The granules obtained were dried at 60° C. for        20 minutes. The dried granules were sifted through 40-mesh        screen.    -   2. The required quantities of Crospovidone and AEROSIL® were        weighed and co-sifted with granules through 40-mesh screen and        blended for 5 minutes to obtain pre-lubricated blend.    -   3. Magnesium stearate was passed through 60-mesh screen and        added to pre-lubricated blend and lubricated for 5 minutes.

TABLE 23 Compression parameters Composition 54 Composition 55 Tooling11.00 mm round 11.00 mm round biconvex punches biconvex punches Hardness7-8 kp 7-8 kp Thickness 6.4-6.5 mm 6.4-6.5 mm Disintegration time NMT* 3minutes NMT* 3 minutes *NMT—Not More Than

Dissolution Profiles of TASIGNA® 50 mg Capsule, Composition 54 and 55 in0.01 N HCl Acid Media and Followed by pH 6.5 FaSSIF Buffer Media.

When tested by using USP apparatus II (paddle); 500 mL of 0.01 N HClmedia for 60 minutes and followed by 900 mL of pH 6.5 FaSSIF buffermedia for 120 minutes at 37±0.5° C. and stirred at 75 rpm, thedissolution profiles of Composition 54 and 55 were compared withTASIGNA® 50 mg capsule in following Table 24. Samples of 5 mL werewithdrawn at 15, 30 and 60 minutes in 0.01 N HCl acid media and 65, 70,75, 90, 105, 120, 150 and 180-minute time points in FaSSIF buffer media.Withdrawn samples were filtered with 0.45 μm nylon membrane filter andthen diluted with dimethyl sulfoxide (DMSO) in 1:1 ratio and analysedusing HPLC system with UV spectrophotometer at a wavelength 230 nm. Theresults of the measurements are given in Table 24 and shown graphicallyin FIG. 9 .

TABLE 24 % of Drug released TASIGNA ® Dissolution Time 50 mg CompositionComposition Media (minutes) Capsule 54 55 0.01 N HCl 0 0 0 0 acid media15 19 37 46 30 56 — — 60 74 64 75 FaSSIF 65 3 — — Buffer 70 2 15 21Stage 75 2 17 20 90 1 20 18 105 3 17 18 120 2 17 17 150 2 17 17 180 2 1516

Example 16 Hot-Melt Extrusion Process Optimization

The process for the preparation of the pharmaceutical compositions ofpresent invention involves an extrusion process followed by aformulation process. Formation of an impurity was observed anddetermined to be directly related to process temperature of hot-meltextrusion employed. Optimization of process temperature, feed rate andscrew speed during hot-melt extrusion was critical in order to reduceformation of impurities. Critical process parameters such as feed rateand screw speed were also found to have a significant impact on criticalproduct attributes of the solid dispersion such as amorphous nature ofnilotinib in solid dispersion.

Impact of different process temperatures on impurity formation innilotinib solid dispersion is given in below Table 25.

TABLE 25 Impurities Known impurity Impurity N- NLT- Unknown Impurity DOxide C UI*-1 UI-2 UI-3 UI-4 UI-5 RRT** 0.68 1.08 1.18 0.822 0.84 0.900.94 0.96 PXRD Process 160 0.04 0.01 0.04 0.03 0.04 ND 0.09 0.02Amorphous Temperature 170 0.04 0.02 0.04 0.03 0.06 0.01 0.14 0.02Amorphous (° C.) 180 0.05 0.01 0.04 0.04 0.05 ND 0.16 0.01 Amorphous 1900.06 0.01 0.03 0.04 0.07 ND 0.24 0.03 Amorphous 200 0.06 0.03 0.03 0.040.06 ND 0.19 0.03 Amorphous *UI = Unknown Impurity; **RRT = RelativeRetention time

Impact of different feed rate and screw speed on impurity formation innilotinib solid dispersion is given in below Table 26.

TABLE 26 Impurities Impurity N- NLT- D UI-1 UI-2 UI-3 UI-4 UI-5 Oxide CFeed RRT Rate Screw 0.68 0.82 0.84 0.9 0.94 0.96 1.08 1.18 (g/min) Speed% of Impurity PXRD 3 325 ND ND 0.03 ND 0.06 ND ND ND Amorphous 4.6 325ND ND 0.02 ND 0.02 ND ND ND Amorphous 4.6 250 ND ND ND ND ND ND ND NDCrystalline 4.6 200 ND ND ND ND ND ND ND ND Crystalline 4.6 150 ND ND NDND ND ND ND ND Crystalline 4.6 100 ND ND ND ND ND ND ND ND Crystalline*UI = Unknown Impurity; RRT = Relative Retention time

Having now fully described this invention, it will be understood bythose of ordinary skill in the art that it can be performed within awide equivalent range of parameters without affecting the scope of theinvention or any embodiment thereof. All publications, patentapplications and patents disclosed herein are incorporated by referencein their entirety.

Unless specified otherwise, all the percentages, portions and ratios inthe present invention are on weight basis.

Unless otherwise indicated, all numbers expressing quantities ofingredients, properties such as molecular weight, reaction conditions,and so forth used in the present specification and associated claims areto be understood as being modified in all instances by the term “about.”Accordingly, unless indicated to the contrary, the numerical parametersset forth in the following specification and attached claims areapproximations that may vary depending upon the desired propertiessought to be obtained by the embodiments of the present invention.Whenever a numerical range with a lower limit and an upper limit isdisclosed, any number and any included range falling within the range isspecifically disclosed. In particular, every range of values (of theform, “from about a to about b,” or, equivalently, “from approximately ato b,” or, equivalently, “from approximately a-b”) disclosed herein isto be understood to set forth every number and range encompassed withinthe broader range of values. Also, the terms in the claims have theirplain, ordinary meaning unless otherwise explicitly and clearly definedby the patentee. Moreover, the indefinite articles “a” or “an,” as usedin the claims, are defined herein to mean one or more than one of theelement that it introduces.

While compositions and methods are described herein in terms of“comprising” various components or steps, the compositions and methodscan also “consist essentially of” or “consist of” the various componentsand steps.

1. A pharmaceutical composition comprising: (i) nilotinib tartrate; (ii) pharmaceutically acceptable carrier selected from the group consisting of hydroxypropyl methyl cellulose acetate succinate (HPMC-AS), polyvinyl pyrrolidine and vinyl acetate (PVP/VA) copolymer, hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl methylcellulose, (HPMC), polyethylene glycol (PEG), hydroxypropyl cellulose (HPC), carboxymethyl cellulose (CMC), polyvinyl pyrrolidine (PVP), and combinations thereof; and (iii) one or more pharmaceutically acceptable excipients; wherein an administered amount equivalent to nilotinib is about 50% less than a dose required for delivering a therapeutically effective amount equivalent to nilotinib in a fasted state using a reference formulation.
 2. The pharmaceutical composition according to claim 1, wherein said nilotinib tartrate is substantially in amorphous form.
 3. The pharmaceutical composition according to claim 1, wherein the weight ratio of the nilotinib tartrate to the pharmaceutically acceptable carrier is from about 1:6 to about 1:1.
 4. The pharmaceutical composition according to claim 1, wherein a dose of nilotinib administered in the pharmaceutical composition is from 125 mg to 150 mg.
 5. The pharmaceutical composition according to claim 1, wherein a dose of nilotinib administered in the pharmaceutical composition is from 175 mg to 200 mg.
 6. The pharmaceutical composition according to claim 1, wherein a dose of nilotinib administered in the reference composition is 300 mg.
 7. The pharmaceutical composition according to claim 1, wherein a dose of nilotinib administered in the reference composition is 400 mg.
 8. The pharmaceutical composition according to claim 1, wherein an amount equivalent to nilotinib in a unit dosage form of said pharmaceutical composition is from 50 mg to 75 mg.
 9. The pharmaceutical composition according to claim 1, wherein an amount equivalent to nilotinib in a unit dosage form of said pharmaceutical composition is from 75 mg to 100 mg.
 10. The pharmaceutical composition according to claim 1, wherein an amount equivalent to nilotinib in a unit dosage form of said pharmaceutical composition is about 75 mg.
 11. The pharmaceutical composition according to claim 1, wherein an amount equivalent to nilotinib in a unit dosage form of said pharmaceutical composition is about 100 mg. 